It is well known that chemotherapy can cure only some cancers in advanced stage, mostly those with an intact p53 pathway. Hematological cancers such as lymphoma and certain forms of leukemia are paradigmatic examples of such scenario. Recent evidence indicates that the efficacy of many of the alkylating and intercalating agents, antimetabolites, topoisomerase, and kinase inhibitors used in cancer therapy is largely due to p53 stabilization and activation consequent to the inhibition of ribosome biogenesis. In this context, innovative drugs specifically hindering ribosome biogenesis showed preclinical activity and are currently in early clinical development in hematological malignancies. The mechanism of p53 stabilization after ribosome biogenesis inhibition is a multistep process, depending on specific factors that can be altered in tumor cells, which can affect the antitumor efficacy of ribosome biogenesis inhibitors (RiBi). In the present review, the basic mechanisms underlying the anticancer activity of RiBi are discussed based on the evidence deriving from available preclinical and clinical studies, with the purpose of defining when and why the treatment with drugs inhibiting ribosomal biogenesis could be highly effective in hematological malignancies. Keywords: Ribosome biogenesis inhibitors, Chemotherapy, Lymphoma, Leukemia, Ribosomal proteins, MDM2, p53, pRb Background selectively hindering the transcription of ribosomal (r) The ribosome biogenesis is defined as the process of RNA, thus inhibiting ribosome biogenesis without hav- building new ribosomes, the intracellular organelles ing genotoxic effects, have been proposed as a new where protein synthesis takes place. therapeutic approach, based on p53 activation [7–12]. In recent years, several studies on the relationship be- However, it is known since long time that chemotherapy tween cell growth and proliferation produced important can cure only some cancers once they reach advanced data regarding the mechanisms linking ribosome biogen- stages. In fact, despite initial responses, the majority of esis, which is at the basis of cell growth, to the progression metastatic solid tumors ultimately progress under chemo- through the cell cycle phases of the proliferating cell. There therapy treatment. Hematological malignancies (such as is now evidence that a perturbed ribosome biogenesis acti- lymphomas and acute leukemias) represent paradigmatic vates a pathway leading to the stabilization and activation examples of the few cancers that can be cured by chemo- of the tumor suppressor protein p53, which in turn induces therapeutic agents and will be the main topic of the cell cycle arrest and/or apoptotic cell death [1–4]. present review . The basic biological characteristic Current evidence indicates that inhibition of ribosome underlying the intrinsic curability of such cancers is that, biogenesis represents a major mechanism by which in a significant fraction of cases, they retain a functional many of the currently used chemotherapeutic drugs p53-mediated response to nucleolar stress arising from (alkylating and intercalating agents, antimetabolites, ribosomal biogenesis inhibition; on the other hand, as a topoisomerase inhibitors) exert their cytotoxic activity matter of fact, the presence of genomic alterations of the on cancer cells [5, 6]. Importantly, a series of new drugs TP53 gene is an established negative prognostic predictor in lymphoma, acute and chronic leukemias treated with chemotherapy regimens [14–17]. * Correspondence: firstname.lastname@example.org; email@example.com European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy DIMES, Università di Bologna, Via Massarenti 9, Bologna, Italy © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 2 of 13 Since p53 stabilization and activation is a multistep binding factor (UBF), are present . For the transcrip- and tightly regulated process, in principle, the prerequis- tion of the 5S rRNA by Pol III, the transcription factors ite for the antitumor efficacy of drugs inhibiting ribo- TFIIIC and TFIIIB are necessary [34–36]. In proliferat- some biogenesis should be the presence in the tumor ing cells, the rate of ribosome biogenesis is enhanced in cells, other than a normally functioning p53, also of order to assure an adequate ribosome complement for those factors necessary for the activation of p53 and the the daughter cells and inhibition of ribosome biogenesis induction of a p53-mediated cell cycle arrest and/or the arrests cell cycle progression . Furthermore, the rate apoptosis. These factors, which control cell cycle pro- of ribosome biogenesis influences the length of the cell gression in normally proliferating cells , are qualita- cycle: higher the level of ribosome biogenesis, more tively and quantitatively altered in the large number of rapid the cell cycle progression . Ribosome biogen- cancers [19, 20], thus influencing the sensitivity to ribo- esis rate in cancer shows high variability, depending on a some biogenesis (RiBi) inhibitors. multiplicity of factors including the activation of specific Therefore, it seems timely to critically review the char- intracellular signaling pathways and deregulated activity acteristics of cancer cells which affect their sensitivity to of oncogenes and tumor suppressors. On the other RiBi inhibitors, with the purpose of highlighting those hand, quantitative and qualitative changes in ribosome parameters which render the treatment with these drugs biogenesis have been shown to facilitate neoplastic appropriate or not in hematological malignancies. For transformation. For a detailed description of the the convenience of the reader, the normal process of relationship between ribosome biogenesis and cancer, ribosome biogenesis will be first briefly described. the reader should refer to [39–44]. In hematological malignancies, such as aggressive lymphoproliferative Ribosome biogenesis neoplasms, it is worth mentioning the oncogenic Ribosomes are ribonucleoprotein particles which are lo- cooperation between the MYC oncogene and the cated in the cytoplasm where, either free or membrane- phosphatidyl-inositol-3-kinase (PI3K) signaling pathway bound, are engaged in protein synthesis. Four types of , which converge in stimulating rRNA synthesis and ribosomal RNA (rRNA) molecules and about 80 differ- ribosome biogenesis . ent ribosomal proteins constitute the ribosome. Ribo- some formation occurs mainly in the nucleolus, being Inhibition of ribosome biogenesis activates the later completed in the nucleoplasm and in the cytoplasm RPs/MDM2/p53 pathway (see for reviews: [21–24]). In the nucleolus, ribosomal Available data indicate that the levels of p53 expression genes are transcribed by RNA polymerase I (Pol I) to and activity are mainly regulated by interactions with generate the 47S rRNA precursor, which undergoes to the tumor suppressor MDM2 (murine double minute 2, site-specific methylation and pseudo uridylation, and and HDM2 in humans). MDM2 is an E3 ubiquitin ligase processing to give rise to the mature 18S, 5.8S, and 28S which negatively controls p53 activity in two ways: by rRNA. The fourth types of rRNA, the 5S rRNA, is syn- binding to the protein and inhibiting its transactivation thesized in the nucleoplasm by RNA polymerase III (Pol activity, and by facilitating its proteasome degradation III) and then imported in the nucleolus together with [47–49]. In normal proliferating cells, the level of p53 is the ribosomal proteins (RPs), whose mRNA is tran- maintained low because of the binding with MDM2 with scribed by RNA polymerase II (Pol II). The assembling of consequent p53 ubiquitination and proteasome digestion rRNA molecules with the RPs constitutes the two sub- . When a perturbation in the ribosome biogenesis units of the mature ribosome, the large 60S and the small occurs (ribosome stress), it results in the binding of sev- 40S subunit. The large 60S subunit is constituted by one eral ribosomal proteins, no longer used for ribosome each of the 28S, 5.8S, and 5S RNA molecules, together building, to MDM2. This binding relieves the inhibitory with 47 ribosomal proteins (RPLs); the small 40S subunit activity of MDM2 toward p53 (see reviews [2–4, 51, 52]) contains only one 18S RNA molecule and 33 ribosomal (Fig. 1). Although there is evidence that RPL5, RPL11, proteins (RPSs) [25, 26]. Both subunits migrate from the and RPL23 play a major role in neutralization of MDM2 nucleolus to the cytoplasm where they form the 80S ribo- activity and in the induction of p53 stabilization [50, 53– some particle. In the process of ribosome biogenesis, more 58], the list of ribosomal proteins (of both large and than 150 non-ribosomal proteins and around 70 small nu- small ribosomal subunit) able to inhibit MDM2 activity cleolar RNAs are involved [27–32]. and to stabilize p53 upon “ribosomal stress” is rapidly For the transcription of the of 47S pre-rRNA, the as- expanding . For a valid binding to MDM2 and its in- sembly of a specific multiprotein complex at the rDNA activation, the RPL11 and RPL5 must form a complex promoter containing Pol I is required. In this complex, with the 5S rRNA and all the components of this com- three basal factors, termed transcription initiation factor plex are necessary for its inhibitory function [59, 60]. I (TIF-I) A, selectivity factor 1 (SL1), and upstream p53 stabilization always causes cell cycle arrest in Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 3 of 13 MDM2 phosphorylation results in increased stability of MDM2 with consequent p53 degradation [69, 70]. As mentioned before, constitutive PI3K signaling is common in lymphoproliferative neoplasms, and PI3K inhibitors are in clinical development in lymphoid cancers. These no- tions could be relevant for designing therapeutic combin- ation strategies aimed at increasing the p53-mediated response to the inhibition of ribosome biogenesis. Development of selective inhibitors of ribosome biogenesis As briefly mentioned before, a strong contribution to p53 activation induced by chemotherapeutic agents is due to the inhibition of ribosomal biogenesis. As re- ported by Burger et al. , a series of drugs currently used for treating solid cancers and hematological malig- nancies inhibit ribosome biogenesis at the level of rRNA transcription and/or at the level of rRNA processing (Table 1). To this list, cyclophosphamide and mycophe- Fig. 1 Schematic representation of the pathway activated by drug- nolic acid should be added. Cyclophosphamide, a widely induced perturbation of rRNA synthesis. Ribosomal proteins (RPs), no used anticancer drug, also inhibits rRNA transcription longer used for ribosome building, bind to MDM2, thus inhibiting its , after being converted to acrolein [72, 73], and the ubiquitin ligase activity toward p53 and the proteasome digestion of immunosuppressant mycophenolic acid has been dem- the tumor suppressor. As a consequence, p53 accumulates and induces onstrated to inhibit the synthesis of rRNA . transcription of p21, PUMA, and BAX. P21 is responsible for the cell cycle arrest by hindering pRb phosphorylation: in fact, hypo-phosphorylated In recent years, several efforts have been made to de- pRb binds to and inhibits the activity of the transcription factor E2F1, velop specific inhibitors of ribosomal biogenesis, in order whose target gene products are necessary for cell cycle progression. to achieve a selective inhibition of rRNA synthesis without The induction of the pro-apoptotic factors PUMA and BAX activates the the genotoxic effects proper of chemotherapeutic drugs. process of apoptotic cell death In this light, it appears to be of particular relevance the CX-5461 molecule which selectively inhibits ribosome proliferating cells and, depending on the quantitative biogenesis, most likely by disrupting the SL-1/rDNA com- level of stabilized p53, also apoptotic cell death [61–63]. plex, promoting a cancer-specific activation of p53. Recent p53 arrests cell cycle progression by inhibiting the phos- preclinical data indicate high activity of CX-5461 in MYC- phorylation of the tumor suppressor retinoblastoma driven lymphoma, providing the rationale for further protein, pRb. In its hypo-phosphorylated form, pRb clinical development of this compound [7, 75, 76]. binds to and inhibits the activity of E2F1, a transcription CX-5361 is currently under phase I clinical trial for the factor whose target genes are necessary for cell cycle treatment of patients with advanced hematologic malig- progression. The inhibition of E2F1 activity by hypo- nancies, including acute myeloid leukemia. phosphorylated pRb reduces the expression of both Finally, there is experimental evidence that a small mo- cyclin E and A, necessary factors for cell cycle progres- lecular compound, BMH-21, and a small-molecule pep- sion from G1 to S phase and from G2 to M phase tide (22mer) also selectively inhibit rDNA transcription. respectively, with consequent cell accumulation in G1 BMH21 binds to GC-rich sequences and inhibits RNA and G2 phase . The induction of apoptotic cell death Pol I activity . It also induces the proteasome- by p53 is a consequence of induced expression of the dependent destruction of the large catalytic subunit in the pro-apoptotic members of the B cell lymphoma 2 (Bcl-2) Pol I complex, as do three other small molecular com- gene family, PUMA, and BAX [63, 65–67](Fig. 1). Finally, pounds, BMH-9, BMH-22, and BMH-23 . The 22mer it should be noted that additional factors may interact targets the interface between RNA polymerase I and Rrn3, with the RPs/MDM2/p53 axis, such as the ARF tumor thus selectively inhibiting the synthesis of rRNA . suppressor and the activation of the PI3K pathway. In fact, ARF loss is a common genetic event in cancer and espe- Factors determining cancer cell sensitivity to drugs cially in aggressive lymphoid neoplasms, resulting in in- inhibiting ribosome biogenesis creased MDM2 activity and increased p53 degradation The p53 status (reviewed in ). On the other hand, MDM2 is a down- Since a major effect of ribosome biogenesis inhibition is stream target of the PI3K-AKT axis, and AKT-induced the activation of p53, the cytostatic and cytotoxic effects Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 4 of 13 Table 1 Drugs used to treat hematological and solid with inactivated p53 in which the synthesis of rRNA was malignancies which are effective or highly effective in the hindered by polymerase I silencing . Also, p53 silen- inhibition of rRNA transcription or processing (modified from cing significantly reduced the antiproliferative effects of Burger et al., 2010)  5-fluorouracil and methotrexate or doxorubicin, in human inibition of rRNA synthesis cancer cell lines harboring wild type (wt) p53 and transcription processing treatment of human leukemia and lymphoma cell lines Alkylating agents: with CX-5461, a selective inhibitor of Pol I transcription , was much more effective in cells with wt p53 in com- Melphalan* + - parison with those with mutated p53 [75, 79]. Cisplatin* + - On the other hand, it is worth noting that although Oxaliplatin* + - p53 stabilization appears to be the main mechanism by Cyclophosphamide*+ - which inhibitors of ribosomal biogenesis exert their cy- Intercalating agents: tostatic and cytotoxic action, there is evidence that these Doxorubicin * + - effects can be also caused in a p53-independent way. Depletion of the catalytic subunit of RNA polymerase I Mitoxantrone * + - inhibited the synthesis of rRNA and hindered cell cycle Actinomycin D * + - progression in cells with inactivated p53, as a conse- Mitomycin C + - quence of downregulation of the transcription factor Antimetabolites: E2F-1. Downregulation of E2F-1 was due to release of Methotrexate * + - the ribosomal protein L11, which inactivated the E2F-1- 5-Fluorouracil - + stabilizing function of the E3 ubiquitin protein ligase MDM2 . Furthermore, CX-5461 can induce p53-in- Topoisomerase inhibitors: dependent G2 checkpoint and apoptosis through activa- Camptothecin - + tion of the ataxia telangiectasia mutated (ATM) and Etoposide* - + ataxia telangiectasia and Rad3-related (ATR) kinase Kinase inhibitors: pathway, in the absence of DNA damage [80, 81]. Flavopiridol* - + Regarding hematological malignancies, there is Roscovitine - + evidence that p53 status is an important factor deter- mining the response to currently used chemotherapy Rapamycin + - regimens for lymphoma and leukemia treatment, which Proteasome inhibitors: are based on drugs hindering ribosome biogenesis . Bortezomib* - + Anthracycline-based polychemotherapy represents the Translation inhibitors: standard therapeutic approach for pediatric acute Homoharringtonine* - + lymphoblastic leukemia (ALL) and multiple lymphoma Mitosis inhibitors: subtypes of the adult [including Hodgkin lymphoma (HL), diffuse large B cell lymphoma (DLBCL), and ana- Vinblastine* - + plastic large T cell lymphoma (ALCL)]. More in detail, rRNA polymerase I inhibitors: the ABVD (doxorubicin, bleomycin, vinblastine, and CX-5461*+ - dacarbazine) and the CHOP (cyclophosphamide, doxo- * drugs currently used or in clinical development for the treatment of rubicin, vincristine, and prednisone) regimens represent lymphomas and leukemia Cyclophosphamide is metabolized to acrolein, which is responsible for the the treatments of choice in HL, DLBCL, and ALCL re- inhibition of rRNA transcription [60, 61] spectively. In general, the cure rates of antracycline- CX-5461 is in phase I clinical trial in patients with haematological based regimens have been proved to be variable, being malignancies and in phase I/II trial in patients with breast cancer high for pediatric ALL and Hodgkin lymphoma [82, 83], of chemotherapeutic agents inhibiting ribosome biogen- intermediate for DLBCL [84–86] and ALCL [87, 88], esis should be obviously affected by the status of p53 and low for in indolent B cell lymphoma . Similar [64, 77, 78]. Several lines of preclinical and clinical evi- considerations apply for myeloid disorders where dence support this notion. Indeed, actinomycin D, at a anthracycline-based polychemotherapy has been shown dose that exclusively hinders rDNA transcription, in- to be effective certain forms of acute myeloid leukemia duced a cell cycle arrest with cell accumulation in G1 (reviewed in [90–92]), whereas chronic myeloid neo- and, to a lesser extent, in G2 phase in p53 proficient cell plasms are considered virtually incurable with standard lines [38, 64] whereas these changes in cell cycle distri- polychemotherapy (reviewed in ). The intrinsic cur- bution appeared to be reduced if cells were previously si- ability of the aforementioned hematologic cancers relies lenced for p53 expression . The same occurs in cells on precise biological characteristics of cancer cells, and Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 5 of 13 the p53 status has been demonstrated to represent an RB status and its implications on the clinical outcome important prognostic factor. after treatment with drugs inhibiting ribosome biogenesis. In line with this concept, the presence of TP53 genomic In a series of breast cancers treated with an adjuvant che- alterations in DLBCL and chronic lymphoid leukemia is a motherapeutic protocol including cyclophosphamide, well-established negative prognostic predictor [14, 16, 94, methotrexate, and 5-fluorouracil, the presence of a wild- 95]. DLBCL harboring alterations of the p53 pathway are type or mutated p53, considered independently of the RB often nonresponsive to CHOP plus rituximab (R) che- status, proved to have a null prognostic value. However, moimmunotherapy and are characterized by shorter over- by excluding the cases with no pRb expression or all survival. In CLL, patients harboring 17p deletions or inactivated-hyper-phosphorylated pRb, the p53 status re- TP53 mutations are refractory to standard chemotherapy sulted the only factor predicting the patient clinical out- and are currently treated with chemo-free treatments in- come with patients with wt TP53 having a much better cluding inhibitors of B cell receptor signaling or bcl-2 in- prognosis compared to those with mutated TP53.Worth hibitors . In acute myeloid leukemia, the presence of of noting, the lack of pRb expression was the only inde- TP53 mutations is a powerful negative prognostic pre- pendent factor predicting a good clinical outcome in pa- dictor, being associated with refractoriness to current tients treated with adjuvant chemotherapy [101, 102]. anthracycline-based induction therapies [92, 97]. Finally, Moreover, an RB loss gene expression signature was dem- the presence of TP53 gene mutations predicts the out- onstrated to be associated with increased pathological come after induction and reinduction chemotherapy in complete response to neoadjuvant chemotherapy in both acute lymphoid leukemia . estrogen-receptor positive and negative breast cancers The prognostic value of genomic alterations of TP53 . Although the role of pRb pathway has not been has been recently evaluated across a wide variety of evaluated as extensively as p53, similar observations were hematological malignancies confirming the role of the reported in hematological malignancies. In anaplastic p53 axis in determining the efficacy of chemotherapy in large cell lymphoma, absence of pRb expression was this setting . observed in 40% of cases and hyperphosphorylation of pRb was detected in a significant fraction of RB positive The pRb status patients, consistent with RB inactivation. Notably, these These experimental and clinical data indicate that wild- alterations correlated with a favorable clinical outcome type TP53 is a necessary requisite for the activation of . In chronic lymphoid leukemia, 13q14 deletion is the mechanisms leading to cell cycle arrest and/or apop- a frequent genomic alteration, and although the specific totic cell death in cancer cells treated with drugs inhibit- pathogenetic role of RB1 loss in the context of 13q14 ing ribosome biogenesis. deletion is yet to be determined, this cytogenetic abnor- There is evidence that this could be mostly true in the mality predicts good clinical outcome following therapy case of a normally functioning pRb pathway. Indeed, the with the FCR (fludarabine, cyclophosphamide, rituxi- absence of pRb could be a major factor conditioning the mab) regimen . sensitivity of cancer cells to the exposure of RiBi inhibi- Similarly, trisomy 12 (resulting in copy number gain of tors, also when the p53 pathway is dysfunctional . Pre- CDK4 with consequent hyperphosphorylation and in- liminary studies on this topic were conducted on solid activation of pRb) is associated with excellent outcomes tumor models, such as breast cancer. In fact, the contem- following chemoimmunotherapy . Of note, the con- porary absence of pRb and functional p53 has been shown temporary presence of 13q14 deletion seems to attenu- to be responsible for a marked reduction of the cell popu- ate the adverse outcome related to the presence of TP53 lation growth after the inhibition of ribosome biogenesis deletions in CLL . Since the RB1 locus is affected in by actinomycin D, 5-fluorouracyl, methotrexate, and less than 50% of CLL cases harboring 13q14 deletions doxorubicin, which was even greater than that observed , it would be interesting to investigate whether spe- in p53 proficient cells [64, 78]. The cause of this increased cific loss of RB1 attenuates the poor prognosis related to sensitivity lies in the complete abrogation of the two cell TP53 alterations. In conclusion, these data taken to- cycle checkpoints in the absence of RB [19, 99, 100]: in gether indicate that (1) the presence of wt p53 associated cells lacking RB, the inhibition of ribosome biogenesis with a normal downstream pRB pathway is an important does not hinder the cell cycle progression, thus leading characteristic which render cancer cells very sensitive to the cells to divide without having reached an appropriate drugs inhibiting ribosome biogenesis and (2) cancer cells ribosome complement. Very rapidly, the reduction of with RB1 loss could be sensitive to ribosome biogenesis ribosome complement becomes incompatible with cell inhibitors irrespective of the p53 status. survival and a progressive increase of apoptotic cell death However, the integrity of the p53/pRb pathway might occurs . These experimental data are consistent with not be the only factor affecting response to ribosomal studies investigating the relationship between the p53 and biogenesis inhibition, as described below. Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 6 of 13 The rate of ribosome biogenesis of the cell Ribosomal protein deletions and mutations Other than arresting cell cycle progression, stabilized Since the main mechanism involved in p53 stabilization p53 may cause programmed cell death by inducing tran- upon ribosome biogenesis inhibition is represented by scription of pro-apoptotic factors [63, 65, 66]. Induction the binding of RPs to MDM2, mutations of ribosomal of apoptosis by inhibitors of ribosome biogenesis de- proteins may constitute another factor influencing the pends on the level of p53 stabilization, apoptosis being response of cancer cells to ribosome biogenesis inhibi- activated only by high amount of stabilized p53. In turn, tors. As reported above, RPL5 and RPL11 play a major the amount of stabilized p53 was shown to be directly role in MDM2 inactivation. However, many other RPs, related to the ribosome biogenesis rate of the cell. This including RPL3, RPL6, RPL23, RPL26, RPL37, RPS7, was demonstrated by using four drugs, which inhibit RPS14, RPS15, RPS19, RPS20, RPS25, RPS26, and rRNA synthesis at different steps: actinomycin D, doxo- RPS27, have been shown to bind to MDM2, thus stabil- rubicin, 5-fluorouracyl, and CX-5461 . In cells char- izing p53 after induction of ribosomal stress (see for a acterized by a high rate of rRNA transcription, the recent and comprehensive review: ). There is in- inhibition of ribosome biogenesis caused a significantly creasing evidence for the presence of ribosomal protein greater degree of p53 stabilization and consequent copy number changes and mutations in many types of greater expression of the pro-apoptotic members of the cancer. Regarding the RPs of the large ribosome subunit, Bcl-2 gene family, PUMA, and BAX, compared to those exome sequencing demonstrated the presence of muta- characterized by a lower baseline rRNA synthesis. Ac- tions of RPL5 in T cell acute lymphoblastic leukemia cordingly, apoptotic cell death occurred in cells with a (T-ALL)  and in glioblastoma , and loss of the high rRNA synthesis and not in cells with a low ribo- 1p22.1 region encompassing the RPL5 gene was found some biogenesis rate, the latter showing only cell cycle in 20% of multiple myeloma cases (MM) . Further- arrest. The tight relationship between the level of p53 more, RPL5 and RPL10 mutations were recently ob- stabilization and the rRNA synthesis rate was due to the served, even though at low frequency, in MM . The fact that, upon ribosome biogenesis inhibition, different frequency of inactivating RPL5 mutations and deletions amounts of RPs, no longer used for ribosome building, was found to be 11% in glioblastoma, 28% in melanoma, bind to MDM2, thus hindering with higher efficiency and 34% in breast cancer patients . In T-ALL, the proteasomal degradation of p53 . Interestingly, in RPL10 and RPL11 mutations have been also described cells with low rRNA synthesis (in which the inhibition of [108, 113] and RPL22 was found to be deleted in about ribosome biogenesis stabilized p53 in a level that was not 10% patients . RPL22 mutations were observed to sufficient for apoptosis induction), the combined treat- occur with high frequency in endometrial [115, 116] and ment with hydroxyurea which activates p53 with a differ- colorectal cancer  with microsatellite instability. ent mechanism allowed to increase the total amount of Regarding the proteins constituting the small ribosome stabilized p53 inducing apoptotic cell death . subunit, whole exome sequencing of chronic lympho- Since the induction of cell death, and not cell cycle cytic leukemia showed recurrent mutations of RPS15 arrest, is the main goal of cancer chemotherapy, these ob- [117, 118] while mutations of RPS20 are associated with servations might be relevant for establishing more effect- colorectal carcinoma . There are still few data on ive and appropriate therapeutic protocols. In fact, this the effect of ribosomal protein deletion or mutations on model implies that ribosome biogenesis inhibitors as sin- the response to chemotherapeutic treatments. Experi- gle agents could be highly effective in p53 wild-type can- ments conducted using cancer cell lines demonstrated cers with a high ribosome biogenesis rate, by inducing that silencing the expression of RPL5 and RPL11 apoptotic cell death, whereas for treating cancers with a strongly reduced the stabilization and activation of p53 low ribosome biogenesis rate, they should be combined caused by selective rRNA transcription inhibitors [120, with drugs capable of stabilizing p53 or inducing apoptosis 121], suggesting that cancers carrying these genetic through different mechanisms. This model applies well in changes should be resistant to chemotherapy based on the setting of TP53 wild-type lymphoproliferative neo- inhibitors of ribosome biogenesis. plasms, where aggressive lymphomas such as DLBCLs, Up to now, the only clinical evidence of the impact of characterized by high ribosomal biogenesis rates , RP genetic changes on chemotherapy resistance based can be cured with standard R-CHOP polychemotherapy on a reduced activation of the RP-MDM2-p53 pathway [84–86], whereas indolent B cell non-Hodgkin lymph- comes from the study by Ljungström et al.  on the omas (such as small lymphocytic lymphoma/chronic relationship between RPS15 mutations and clinical out- lymphoid leukemia, marginal zone lymphoma, and follicu- come of patients with chronic lymphocytic leukemia. lar lymphomas), characterized by low ribosomal biogen- The authors found that patients with RPS15 mutations, esis rates , are virtually incurable with the same type but carrying wild-type TP53, treated with standard of polychemotherapy . chemoimmunotherapy (combination of fludarabine, Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 7 of 13 cyclophosphamide, and rituximab), had a shorter 10- adverse outcome in TP53 wild-type patients (manu- year survival compared with patients without mutated script submitted). RPS15, and an overall survival similar to patients charac- In conclusion, although preliminary evidence suggests terized by other adverse-prognostic markers. In the same that RP mutations could provide cancer cells with alter- study, the authors, using a human tumor cell line, dem- native mechanisms to inactivate p53-mediated responses onstrated that transiently expressed mutant RPS15 re- to nucleolar stress, more studies are needed on the oc- duced the expression of p53 due to an increased currence of RP gene deletions and mutations in cancer ubiquitin-mediated p53 degradation in comparison with cells and their influence on p53 stabilization and thera- cells carrying wild-type RPS15. It could be possible that peutic response after treatment with ribosome biogen- mutated RPS15 is not capable of neutralizing the esis inhibitors. MDM2-mediated p53 digestion , thus reducing the induction of stabilized p53 upon chemotherapy treat- Mutated nucleophosmin ment. In line with these data, our group recently found Nucleophosmin (NPM1), also called protein B23, numa- non-recurrent mutations of multiple RP genes in a trin, and NO38, is a non-ribosomal phosphoprotein, pri- significant fraction of DLBCL cases (> 10%) and mary located in the nucleolus [123, 124]. NPM1 shuttles RPS12 and RPL22 deletions in up to 20% of cases. between the nucleolus and the cytoplasm  and ex- Furthermore, our preliminary data indicate that these erts a series of different biochemical functions, some of alterations are mutually exclusive with TP53 muta- them being independent of ribosome biogenesis (see for tions and that RP mutations could be associated with review [126–129]). Regarding the relationship between Table 2 Overview of genomic alterations involved in the regulation of the RP/MDM2/p53 axis in hematologic malignancies Genomic alteration Disease type Incidence of the alteration Prognostic impact Proposed Mechanism Reference TP53 mutation DLBCL 22%-24% Poor Impaired p53 mediated response [14, 146] to nucleolar stress CLL 7-9% Poor [94, 147–149] ALCL 8% Poor  ALL 14-15% Poor [15, 150] AML 5%-9% Poor [92, 151] MM <5% Poor  TP53 deletion DLBCL 12% Poor  CLL 5-12% Poor [147, 148] ALL 11% Poor  MM 9.5% Poor  ARF deletion DLBCL 35% Poor Increased MDM2-dependent p53  degradation FL 8% Poor  ALL 14-15% Poor [15, 150, 155] RB1 loss DLBCL 11% Neutral Loss of G1/S checkpoint  CLL 20% Neutral  ALCL 40% Good  ALL 9% Neutral [158, 159] RPS15 mutation CLL 19% (RELAPSE) Poor Impaired p53 mediated response  to nucleolar stress RPL5 mutation MM Sporadic NE  T-ALL <5% NE  RPL5 deletion MM 20% Poor  RPL10 mutation T-ALL 5% NE  RPL22 deletion T-ALL 10% NE  NPM1 mutation AML 53% Good* Increased sensitivity to nucleolar stress  NPM1-ALK ALCL 55% Good  Abbreviations: NE (not evaluated), DLBCL (diffuse large B-cell lymphoma), FL (Follicular lymphoma), CLL (chronic lymphoid leukemia), ALCL (anaplastic large T-cell lymphoma), ALL (acute lymphoid leukemia), T-ALL (T-cell acute lymphoid leukemia), MM (Multiple Myeloma), AML (acute myeloid leukemia) *Associated with good prognosis in the absence of FLT3 genomic alterations Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 8 of 13 NPM1 and ribosome biogenesis, there is evidence that containing anthracyclines and cytarabine [91, 141]. This NPM1 plays a role in rRNA maturation  and its is probably due to the fact that leukemic cells with mu- chaperone activity may facilitate the process of ribosome tated NPM1 maintain a functional wild-type p53 . assembly . Furthermore, NPM1 has been shown to In line with this data, a recent study reported that pa- be an important mediator, connecting the BCR-ABL net- tients with AML with mutated NPM1, not eligible for work to ribosome biogenesis and, hence, protein synthe- intensive chemotherapy or with refractory or relapsed sis and cell growth in chronic myelogenous leukemia disease, may be successfully treated with actinomycin D, . Lastly, in proliferating cells, the amount of NPM1 at the same dose as that used for low-risk gestational is directly related to the rRNA transcription rate  trophoblastic tumors . The rationale at the basis of and in human cancer cell lines to the nucleolar size and this therapeutic strategy is that leukemic cells with mu- to the rate of cell proliferation . tated NPM1 may have a more vulnerable nucleolus to Quantitative and qualitative changes of NPM1 have the stress induced by the inhibition of ribosome biogen- been reported to occur in many human malignancies esis, resulting in a very strong p53-mediated response. (see for review ). Heterozygous NPM1 mutations NPM1 is also a frequent target of chromosomal translo- were observed to occur in about 30% of patients with cations. The NPM1-ALK (anaplastic lymphoma kinase) acute myeloid leukemia (AML) and, with very few ex- fusion protein is the hallmark of ALK-positive anaplastic ceptions, were restricted to exon 12 [135, 136]. Mutant large cell lymphoma (reviewed in ). The NPM1- NPM1 is delocalized to the cytoplasm (NPM1c+) while ALK fusion protein activates a series of cellular signaling the amount of wild-type NPM1 located in the nucleolus pathways boosting lymphomagenesis while inhibiting is reduced as a consequence of haploinsufficiency and p53 activity with MDM2 and JNK (c-Jun N-terminal formation of heterodimers with mutated NPM1 in the kinase) dependent mechanisms . Therefore, ALK- cytoplasm . Importantly, NPM1 mutations are positive ALCL often retain a functional p53-mediated re- mutually exclusive with TP53 mutations  and con- sponse to nucleolar stress, and accordingly TP53 muta- sistent with this observation the presence of NPM1c+ tions are rare in NPM1-ALK-positive ALCL. In line with inhibits p53-mediated responses: in fact cytoplasmic these findings, NPM1-ALK-positive ALCL are character- NPM1 localization determines sequestration of ARF ized by a better prognosis following conventional CHOP tumor suppressor in the cytoplasm, therefore limiting compared to their ALK negative counterparts. Further the interaction of ARF with MDM2 with consequent in- investigations on the relationship between the functional creased p53 degradation [138–140]. It is noteworthy that state of the nucleolus and the response to ribosome bio- from the clinical point of view acute myeloid leukemia genesis inhibitors should be conducted with the aim of with mutated NPM1 is characterized by a better progno- establishing therapeutic protocols based on selective in- sis due to a higher remission rate after chemotherapy hibition of ribosome biogenesis. Fig. 2 Schematic model representing the relationship between certain intrinsic cancer cell characteristics and curability of hematologic malignancies following chemotherapy based on drugs inhibiting ribosome biogenesis. Cancers with wild-type TP53, high ribosome biogenesis rate, loss of retinoblastoma protein, mutated NPM1 are characterized by good prognosis following chemotherapy (this is the case of TP53 wild-type HL, ALCL, DLBCL, NPM1c+ AML). At the opposite side of the spectrum, cancers characterized by mutant TP53 or mutant ribosomal proteins genes are associated with a low cure rate (certain forms of DLBCL, MM, T-ALL, CLL, AML). In the middle, cancers with low ribosomal biogenesis rate and wild-type TP53 harbor an intermediate cure rate (FL, other indolent B cell lymphoma subtypes) Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 9 of 13 Conclusions Funding This work was supported by the Roberto and Cornelia Pallotti Legacy for Despite the advent of personalized medicine, current Cancer Research. treatment algorithms do not take into account important biological parameters which have been demonstrated to Availability of data and materials Data sharing is not applicable to this article as no datasets were generated affect the cancer response to chemotherapeutic agents or analyzed during the current study. (these factors are summarized in Table 2)[14–16, 91, 92, 94, 103, 108, 110, 111, 118, 146–161]. There is now evi- Authors’ contributions ED conceived the structure of the review and wrote the manuscript; AL dence that the efficacy of many of the chemotherapeutic helped with the manuscript writing; DT conceived the structure of the drugs used for cancer treatment is related to p53 review and wrote the manuscript. All authors read and approved the final stabilization consequent to ribosome biogenesis inhib- manuscript. ition (Fig. 1), and efforts are ongoing to develop new Ethics approval and consent to participate drugs that can selectively target ribosome biogenesis, Not applicable without having the genotoxic effects proper of standard Competing interests chemotherapeutic agents. In this context, it is worth The authors declare that they have no competing interests. mentioning the selective inhibitor of rRNA transcription, the CX-5461 molecule [7, 75], which may represent a Publisher’sNote new, very interesting strategy for cancer therapy [12, Springer Nature remains neutral with regard to jurisdictional claims in 162–164]. In this research field, other molecular com- published maps and institutional affiliations. pounds specifically hindering rDNA transcription have Received: 16 February 2018 Accepted: 26 April 2018 been proposed, demonstrating the increasing interest in this new therapeutic approach [9–11, 165]. On the other References hand, as reported in the present review, a series of ex- 1. Mayer C, Grummt I. Cellular stress and nucleolar function. Cell Cycle. 2005;4: perimental and clinical data indicate that human tumors 1036–8. are characterized by several genomic alterations deter- 2. Deisenroth C, Zhang Y. Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway. Oncogene. 2010;29:4253–60. mining a highly variable response to the treatment with 3. Bursac S, Brdovcak MC, Donati G, Volarevic S. Activation of the tumor ribosome biogenesis inhibitors. In fact, several mecha- suppressor p53 upon impairment of ribosome biogenesis. Biochim Biophys nisms converge in attenuating the anticancer activity of Acta. 2014;1842(6):817–30. 4. Golomb L, Volarevic S, Oren M. p53 and ribosome biogenesis stress: the ribosome biogenesis inhibitors, mostly by reducing the essentials. FEBS Lett. 2014;588(16):2571–9. amount of stabilized p53 and/or the extent of apoptotic 5. Burger K, Mühl B, Harasim T, Rohrmoser M, Malamoussi A, Orban M, et al. responses to RIBi inhibitor-dependent nucleolar stress Chemotherapeutic drugs inhibit ribosome biogenesis at various levels. J Biol Chem. 2010;285(16):12416–25. (Table 2). Accurate knowledge of these mechanisms 6. Burger K, Eick D. Functional ribosome biogenesis is a prerequisite for p53 could provide the rationale for treatment strategies able destabilization: impact of chemotherapy on nucleolar functions and RNA to by-pass resistance to RIBi inhibitors, such as combi- metabolism. Biol Chem. 2013;394(9):1133–43. 7. Drygin D, Lin A, Bliesath J, Ho CB, O'Brien SE, Proffitt C, et al. Targeting RNA nations with MDM2 inhibitors or small molecule inhibi- polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA tors of phosphatidyl-inositol-3-kinase (PI3K) pathway or synthesis and solid tumor growth. Cancer Res. 2011;71(4):1418–30. antiapoptotic proteins such as bcl-2. The main charac- 8. Hannan RD, Drygin D, Pearson RB. Targeting RNA polymerase I transcription and the nucleolus for cancer therapy. Expert Opin Ther Targets. 2013;17(8): teristics influencing the response of hematologic malig- 873–8. nancies to drugs inhibiting ribosome biogenesis are 9. Peltonen K, Colis L, Liu H, Jäämaa S, Zhang Z, Af Hällström T, et al. Small summarized in Fig. 2. These characteristics should be Molecule BMH-Compounds That Inhibit RNA Polymerase I and Cause Nucleolar Stress. Mol Cancer Ther. 2014;13:2537–46. considered and evaluated in advance, in order to predict 10. Peltonen K, Colis L, Liu H, Trivedi R, Moubarek MS, Moore HM, et al. A the degree of therapeutic response, especially when targeting modality for destruction of RNA polymerase I that possesses using selective inhibitors of ribosome biogenesis. anticancer activity. Cancer Cell. 2014;25:77–90. 11. Rothblum K, Hu Q, Penrod Y, Rothblum LI. Selective inhibition of rDNA transcription by a small-molecule peptide that targets the interface Abbreviations between RNA polymerase I and Rrn3. Mol Cancer Res. 2014;12:1586–96. ABVD: Doxorubicin, bleomycin, vinblastine, and dacarbazine; ALCL: Anaplastic 12. Woods SJ, Hannan KM, Pearson RB, Hannan RD. The nucleolus as a large cell lymphoma; ALK: Anaplastic lymphoma kinase; ALL: Acute fundamental regulator of the p53 response and a new target for cancer lymphoblastic leukemia; BAX: Bcl-2-associated X protein; Bcl-2: B cell therapy. Biochim Biophys Acta. 2015;1849(7):821–9. lymphoma 2; CHOP: Cyclophosphamide, doxorubicin, vincristine, and 13. Savage P, Stebbing J, Bower M, Crook T. Why does cytotoxic chemotherapy prednisone; DLBCL: Diffuse large B cell lymphoma; DRB: Dichloro- cure only some cancers? Nat Clin Pract Oncol. 2009;6(1):43–52. ribofuranosylbenzimidazole; FCR: Fludarabine, cyclophosphamide, rituximab; 14. Zenz T, Kreuz M, Fuge M, Klapper W, Horn H, Staiger AM, German High- HL: Hodgkin lymphoma; JNK: c-Jun N-terminal kinase; MDM2: Murine double Grade Non-Hodgkin Lymphoma Study Group (DSHNHL), et al. TP53 minute 2; NPM1: Nucleophosmin; Pol I: RNA polymerase I; Pol II: RNA polymerase mutation and survival in aggressive B cell lymphoma. Int J Cancer. 2017; II; Pol III: RNA polymerase III; pRb: Retinoblastoma protein; PUMA: P53 upregulated 141(7):1381–8. modulator of apoptosis; R: Rituximab; RiBi: Ribosome biogenesis; RPLs: Ribosomal 15. Stengel A, Kern W, Haferlach T, Meggendorfer M, Fasan A, Haferlach C. The proteins of the large subunit; RPs: Ribosomal proteins; RPSs: Ribosomal proteins of impact of TP53 mutations and TP53 deletions on survival varies between the small subunit; SL1: Selectivity factor 1; TIF-I: Transcription initiation factor I; AML, ALL, MDS and CLL: an analysis of 3307 cases. Leukemia. 2017;31(3): TP53: Tumor protein 53; UBF: Upstream binding factor 705–11. Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 10 of 13 16. Xu-Monette ZY, Wu L, Visco C, Tai YC, Tzankov A, Liu WM, et al. Mutational 44. Bustelo XR, Dosil M. Ribosome biogenesis and cancer: basic and profile and prognostic significance of TP53 in diffuse large B-cell lymphoma translational challenges. Curr Opin Genet Dev. 2018;48:22–9. patients treated with R-CHOP: report from an International DLBCL 45. Sander S, Calado DP, Srinivasan L, et al. Synergy between PI3K signaling and Rituximab-CHOP Consortium Program Study. Blood. 2012;120(19):3986–96. MYC in Burkitt lymphomagenesis. Cancer Cell. 2012;22(2):167–79. 17. Eskelund CW, Dahl C, Hansen JW, Westman M, Kolstad A, Pedersen LB, et al. 46. Chan JC, Hannan KM, Riddell K, Ng PY, Peck A, Lee RS, Hung S. AKT TP53 mutations identify younger mantle cell lymphoma patients who do promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome not benefit from intensive chemoimmunotherapy. Blood. 2017;130(17): biogenesis in cancer. Sci Signal. 2011;4(188):ra56. 1903–10. 47. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 18. David-Pfeuty T. The flexible evolutionary anchorage-dependent Pardee’s oncogene product forms a complex with the p53 protein and inhibits restriction point of mammalian cells: how its deregulation may lead to p53-mediated transactivation. Cell. 1992;69:1237–45. cancer. Biochim Biophys Acta. 2006;1765:38–66. 48. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation 19. Sherr CJ. Cancer cell cycles. Science. 1996;274:1672–7. of p53. Nature. 1997;387:296–9. 20. Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 2000; 49. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. 60:3689–95. Nature. 1997;387:299–303. 21. Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR 50. Ljungman M. Dial 9-1-1 for p53: mechanisms of p53 activation by cellular coordinates transcription by all three classes of nuclear RNA polymerases. stress. Neoplasia. 2000;2(3):208–25. Oncogene. 2006;25(48):6384–91. 51. Zhang Y, Lu H. Signaling to p53: ribosomal proteins find their way. Cancer 22. Kopp K, Gasiorowski JZ, Chen D, Gilmore R, Norton JT, Wang C, et al. Pol I Cell. 2009;16:369–77. transcription and pre-rRNA processing are coordinated in a transcription- 52. Stępiński D. Nucleolus-derived mediators in oncogenic stress response and dependent manner in mammalian cells. Mol Biol Cell. 2007;18(2):394–403. activation of p53-dependent pathways. Histochem Cell Biol. 2016;146(2): 23. Lempiäinen H, Shore D. Growth control and ribosome biogenesis. Curr Opin 119–39. Cell Biol. 2009;21(6):855–63. 53. Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA, et al. Ribosomal 24. Grummt I. Wisely chosen paths–regulation of rRNA synthesis. FEBS J. 2010; protein L11 negatively regulates oncoprotein MDM2 and mediates a 277(22):4626–39. p53-dependent ribosomal-stress checkpoint pathway. Mol Cell Biol. 25. Vladimirov SN, Ivanov AV, Karpova GG, Musolyamov AK, Egorov TA, Thiede 2003;23(23):8902–12. B, et al. Characterization of the human small-ribosomal-subunit proteins by 54. Lohrum MA, Ludwig RL, Kubbutat MH, Hanlon M, Vousden KH. N-terminal and internal sequencing, and mass spectrometry. Eur J Biochem. Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell. 1996;239(1):144–9. 2003;3(6):577–87. 26. Odintsova TI, Müller EC, Ivanov AV, Egorov TA, Bienert R, Vladimirov SN, 55. Bhat KP, Itahana K, Jin A, Zhang Y. Essential role of ribosomal protein L11 in et al. Characterization and analysis of posttranslational modifications of the mediating growth inhibition-induced p53 activation. EMBO J. 2004;23(12): human large cytoplasmic ribosomal subunit proteins by mass spectrometry 2402–12. and Edman sequencing. J Protein Chem. 2003;22(3):249–58. 56. Dai MS, Lu H. Inhibition of MDM2-mediated p53 ubiquitination and 27. Fatica A, Tollervey D. Making ribosomes. Curr Opin Cell Biol. 2002;14(3):313–8. degradation by ribosomal protein L5. J Biol Chem. 2004;279(43):44475–82. 28. Fromont-Racine M, Senger B, Saveanu C, Fasiolo F. Ribosome assembly in 57. Dai MS, Zeng SX, Jin Y, Sun XX, David L, Lu H. Ribosomal protein L23 eukaryotes. Gene. 2003;313:17–42. activates p53 by inhibiting MDM2 function in response to ribosomal 29. Tschochner H, Hurt E. Pre-ribosomes on the road from the nucleolus to the perturbation but not to translation inhibition. Mol Cell Biol. 2004;24(17): cytoplasm. Trends Cell Biol. 2003;13(5):255–63. 7654–68. 30. Chédin S, Laferté A, Hoang T, Lafontaine DL, Riva M, Carles CI. ribosome 58. Jin A, Itahana K, O'Keefe K, Zhang Y. Inhibition of HDM2 and activation of synthesis controlled by pol I transcription? Cell Cycle. 2007;6(1):11–5. p53 by ribosomal protein L23. Mol Cell Biol. 2004;24(17):7669–80. 31. Lam YW, Lamond AI, Mann M, Andersen JS. Analysis of nucleolar protein 59. Donati G, Peddigari S, Mercer CA, Thomas G. 5S ribosomal RNA is an dynamics reveals the nuclear degradation of ribosomal proteins. Curr Biol. essential component of a nascent ribosomal precursor complex that 2007;17(9):749–60. regulates the Hdm2-p53 checkpoint. Cell Rep. 2013;4:87–98. 32. Kressler D, Hurt E, Bassler J. Driving ribosome assembly. Biochim Biophys 60. Sloan KE, Bohnsack MT, Watkins NJ. The 5S RNP couples p53 homeostasis to Acta. 2010;1803(6):673–83. ribosome biogenesis and nucleolar stress. Cell Rep. 2013;5:237–47. 33. Grummt I. Life on a planet of its own: regulation of RNA polymerase I 61. Pestov DG, Strezoska Z, Lau LF. Evidence of p53-dependent cross-talk transcription in the nucleolus. Genes Dev. 2003;17(14):1691–702. between ribosome biogenesis and the cell cycle: effects of nucleolar 34. White RJ. RNA polymerase III transcription and cancer. Oncogene. 2004; protein Bop1 on G(1)/S transition. Mol Cell Biol. 2001;21(13):4246–55. 23(18):3208–16. 62. Yuan X, Zhou Y, Casanova E, Chai M, Kiss E, Gröne HJ, et al. Genetic 35. White RJ. RNA polymerases I and III, growth control and cancer. Nat Rev inactivation of the transcription factor TIF-IA leads to nucleolar disruption, Mol Cell Biol. 2005;6(1):69–78. cell cycle arrest, and p53-mediated apoptosis. Mol Cell. 2005;19(1):77–87. 36. Goodfellow SJ, White RJ. Regulation of RNA polymerase III transcription 63. Scala F, Brighenti E, Govoni M, Imbrogno E, Fornari F, Treré D, et al. Direct during mammalian cell growth. Cell Cycle. 2007;6(19):2323–6. relationship between the level of p53 stabilization induced by rRNA synthesis-inhibiting drugs and the cell ribosome biogenesis rate. Oncogene. 37. Volarevic S, Stewart MJ, Ledermann B, Zilberman F, Terracciano L, Montini E, 2016;35(8):977–89. et al. Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6. Science. 2000;288:2045–7. 64. Montanaro L, Mazzini G, Barbieri S, Vici M, Nardi-Pantoli A, Govoni M, et al. 38. Derenzini M, Montanaro L, Chillà A, Tosti E, Vici M, Barbieri S, et al. Key role Different effects of ribosome biogenesis inhibition on cell proliferation in of the achievement of an appropriate ribosomal RNA complement for G1-S retinoblastoma protein- and p53-deficient and proficient human phase transition in H4-II-E-C3 rat hepatoma cells. J Cell Physiol. 2005;202(2): osteosarcoma cell lines. Cell Prolif. 2007;40(4):532–49. 483–91. 65. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell 39. Montanaro L, Treré D, Derenzini M. Changes in ribosome biogenesis may Sci. 2003;116(Pt 20):4077–85. induce cancer by down-regulating the cell tumor suppressor potential. 66. Jin S, Levine AJ. The p53 functional circuit. J Cell Sci. 2001;114(Pt 23):4139–40. Biochim Biophys Acta. 2012;1825(1):101–10. 67. Vousden KH, Prives C. Blinded by the Light: The Growing Complexity of 40. Goudarzi KM, Lindström MS. Role of ribosomal protein mutations in tumor p53. Cell. 2009;137(3):413–31. development (Review). Int J Oncol. 2016;48(4):1313–24. 68. Tessoulin B, Eveillard M, Lok A, Chiron D, Moreau P, Amiot M, et al. p53 41. Orsolic I, Jurada D, Pullen N, Oren M, Eliopoulos AG, Volarevic S. The dysregulation in B-cell malignancies: More than a single gene in the relationship between the nucleolus and cancer: Current evidence and pathway to hell. Blood Rev. 2017;31(4):251–9. emerging paradigms. Semin Cancer Biol. 2016;37-38:36–50. 69. Ogawara Y, Kishishita S, Obata T, Isazawa Y. Akt enhances Mdm2-mediated 42. Derenzini M, Montanaro L, Trerè D. Ribosome biogenesis and cancer. Acta ubiquitination and degradation of p53. J Biol Chem. 2002;277(24):21843–50. Histochem. 2017;119(3):190–7. 70. Feng J, Tamaskovic R, Yang Z, Brazil DP, Merlo A, Hess D, Hemmings BA. 43. Pelletier J, Thomas G, Volarević S. Ribosome biogenesis in cancer: new Stabilization of Mdm2 via decreased ubiquitination is mediated by protein players and therapeutic avenues. Nat Rev Cancer. 2018;18(1):51–63. kinase B/Akt-dependent phosphorylation. J Biol Chem. 2004;279(34):35510–7. Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 11 of 13 71. Wang HT, Chen TY, Weng CW, Yang CH, Tang MS. Acrolein preferentially 95. Byrd JC, Gribben JG, Peterson BL, Grever MR, Lozanski G, Lucas DM, et al. damages nucleolus eliciting ribosomal stress and apoptosis in human Select high-risk genetic features predict earlier progression following cancer cells. Oncotarget. 2016;7(49):80450–64. chemoimmunotherapy with fludarabine and rituximab in chronic 72. Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Characterising lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol. and avoiding the problem. Drugs. 1991;42:781–95. 2006;24(3):437–43. 96. Eichhorst B, Hallek M. Prognostication of chronic lymphocytic leukemia in 73. Boor PJ. Allylamine cardiotoxicity: metabolism and mechanism. Adv Exp Med Biol. 1983;161:533–41. the era of new agents. Hematology Am Soc Hematol Educ Program. 2016; 2016(1):149–55. 74. Sun XX, Dai MS, Lu H. Mycophenolic acid activation of p53 requires ribosomal proteins L5 and L11. J Biol Chem. 2008;283(18):12387–92. 97. Kadia TM, Jain P, Ravandi F, Garcia-Manero G, Andreef M, Takahashi K, et al. 75. Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer Clinicomolecular characteristics, response to therapy, and outcomes. Cancer. specific activation of p53. Cancer Cell. 2012;22:51–65. 92 2016; https://doi.org/10.1002/cncr.30203. 76. Drygin D, Rice WG, Grummt I. The RNA polymerase I transcription 98. Forero-Castro M, Robledo C, Benito R, Bodega-Mayor I, Rapado I, machinery: an emerging target for the treatment of cancer. Annu Rev Hernández-Sánchez M, et al. Mutations in TP53 and JAK2 are independent Pharmacol Toxicol. 2010;50:131–56. prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia. Br J Cancer. 2017;117(2):256–65. 77. Derenzini M, Donati G, Mazzini G, Montanaro L, Vici M, Ceccarelli C, et al. 99. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995; Loss of retinoblastoma tumor suppressor protein makes human breast 81:323–30. cancer cells more sensitive to antimetabolite exposure. Clin Cancer Res. 100. Flatt PM, Tang LJ, Scatena CD, Szak ST, Pietenpol JA. p53 regulation of G(2) 2008;14(7):2199–209. checkpoint is retinoblastoma protein dependent. Mol Cell Biol. 2000;20(12): 78. Derenzini M, Brighenti E, Donati G, Vici M, Ceccarelli C, Santini D, et al. The 4210–23. p53-mediated sensitivity of cancer cells to chemotherapeutic agents is conditioned by the status of the retinoblastoma protein. J Pathol. 2009; 101. Treré D, Brighenti E, Donati G, Ceccarelli C, Santini D, Taffurelli M, et al. High 219(3):373–82. prevalence of retinoblastoma protein loss in triple-negative breast cancers 79. Donati G, Brighenti E, Vici M, Mazzini G, Treré D, Montanaro L, et al. and its association with a good prognosis in patients treated with adjuvant Selective inhibition of rRNA transcription downregulates E2F-1: a new p53- chemotherapy. Ann Oncol. 2009;20(11):1818–23. independent mechanism linking cell growth to cell proliferation. J Cell Sci. 102. Witkiewicz AK, Ertel A, McFalls J, Valsecchi ME, Schwartz G, Knudsen ES. RB- 2011;124(Pt 17):3017–28. pathway disruption is associated with improved response to neoadjuvant 80. Negi SS, Brown P. rRNA synthesis inhibitor, CX-5461, activates ATM/ATR chemotherapy in breast cancer. Clin Cancer Res. 2012;18(18):5110–22. pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and 103. Rassidakis GZ, Lai R, Herling M, Cromwell C, Schmitt-Graeff A, Medeiros LJ. induces apoptosis. Oncotarget. 2015 Jul 20;6(20):18094–104. Retinoblastoma protein is frequently absent or phosphorylated in anaplastic large-cell lymphoma. Am J Pathol. 2004;164(6):2259–67. 81. Quin J, Chan KT, Devlin JR, Cameron DP, Diesch J, Cullinane C, et al. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates 104. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, et al. Long-term non-canonical ATM/ATR signaling. Oncotarget. 2016;7(31):49800–18. remissions after FCR chemoimmunotherapy in previously untreated patients 82. Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. N with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208–15. Engl J Med. 2015;373(16):1541–52. 105. Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, et al. A 83. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, comprehensive evaluation of the prognostic significance of 13q deletions in et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010;148(4): MOPP alternating with ABVD. N Engl J Med. 1992;327(21):1478–84. 544–50. 84. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, et al. 106. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Comparison of a standard regimen (CHOP) with three intensive Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl Med. 2000;343(26):1910–6. JMed. 1993;328(14):1002–6. 107. Crocker J, Nar P. Nucleolar organizer regions in lymphomas. J Pathol. 1987; 151(2):111–8. 85. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients 108. De Keersmaecker K, Atak ZK, Li N, Vicente C, Patchett S, Girardi T, et al. with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 86. Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. and RPL10 in T-cell acute lymphoblastic leukemia. Nat Genet. 2013;45(2): MabThera International Trial Group. CHOP-like chemotherapy plus rituximab 186–90. versus CHOP-like chemotherapy alone in young patients with good-prognosis 109. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera et al. Discovery and saturation analysis of cancer genes across 21 tumour International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379–91. types. Nature. 2014;505:495–501. 87. Chihara D, Fanale MA. Management of Anaplastic Large Cell Lymphoma. 110. Hofman IJ, van Duin M, De Bruyne E, Fancello L, Mulligan G, Geerdens E, Hematol Oncol Clin North Am. 2017;31(2):209–22. et al. RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its 88. Vose J, Armitage J, Weisenburger D. International T-Cell Lymphoma Project. expression is linked to bortezomib response. Leukemia. 2017;31(8):1706–14. International peripheral T-cell and natural killer/T-cell lymphoma study: 111. Hofman IJF, Patchett S, van Duin M, Geerdens E, Verbeeck J, Michaux L, pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124–30. et al. Low frequency mutations in ribosomal proteins RPL10 and RPL5 in 89. Lunning MA, Vose JM. Management of indolent lymphoma: where are we multiple myeloma. Haematologica. 2017;102(8):e317–20. now and where are we going. Blood Rev. 2012;26(6):279–88. 112. Fancello L, Kampen KR, Hofman IJ, Verbeeck J, De Keersmaecker K. The 90. Murphy T, KWL Y. Cytarabine and daunorubicin for the treatment of acute ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in myeloid leukemia. Expert Opin Pharmacother. 2017;18(16):1765–80. multiple cancer types. Oncotarget. 2017;8(9):14462–78. 91. Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, et al. 113. Tzoneva G, Perez-Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta German-Austrian Acute Myeloid Leukemia Study Group. Mutations and M, et al. Activating mutations in the NT5C2 nucleotidase gene drive treatment outcome in cytogenetically normal acute myeloid leukemia. N chemotherapy resistance in relapsed ALL. Nat Med. 2013;19:368–71. Engl J Med. 2008;358(18):1909–18. 114. Rao S, Lee SY, Gutierrez A, Perrigoue J, Thapa RJ, Tu Z, et al. Inactivation of 92. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, ribosomal protein L22 promotes transformation by induction of the et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N stemness factor, Lin28B. Blood. 2012;120:3764–73. Engl J Med. 2016;374(23):2209–21. 115. Novetsky AP, Zighelboim I, Thompson DM Jr, Powell MA, Mutch DG, 93. Goldman JM. Chronic myeloid leukemia: a historical perspective. Semin Goodfellow PJ. Frequent mutations in the RPL22 gene and its clinical and Hematol. 2010;47(4):302–11. functional implications. Gynecol Oncol. 2013;128(3):470–4. 94. Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, et al. TP53 116. Ferreira AM, Tuominen I, van Dijk-Bos K, Sanjabi B, van der Sluis T, van der mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010; Zee AG, et al. High frequency of RPL22 mutations in microsatellite-unstable 28(29):4473–9. colorectal and endometrial tumours. Hum Mutat. 2014;35:1442–5. Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 12 of 13 117. Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. 141. Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker FG, Corbacioglu A, et al. Mutations driving CLL and their evolution in progression and relapse. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger Nature. 2015;526:525–30. adults with acute myeloid leukemia and normal cytogenetics: interaction 118. Ljungström V, Cortese D, Young E, Pandzic T, Mansouri L, Plevova K, et al. with other gene mutations. Blood. 2005;106(12):3740–6. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: 142. Falini B, Brunetti L, Martelli MP. Dactinomycin in NPM1-Mutated Acute clinical impact of recurrent RPS15 mutations. Blood. 2016;127(8):1007–16. Myeloid Leukemia. N Engl J Med. 2015;373(12):1180–2. 119. Nieminen TT, O’Donohue MF, Wu Y, Lohi H, Scherer SW, Paterson AD, et al. 143. Werner MT, Zhao C, Zhang Q, Wasik MA. Nucleophosmin-anaplastic Germline mutation of RPS20, encoding a ribosomal protein, causes lymphoma kinase: the ultimate oncogene and therapeutic target. Blood. predisposition to hereditary nonpolyposis colorectal carcinoma without 2017;129(7):823–31. DNA mismatch repair deficiency. Gastroenterology. 2014;147:595–8. 144. Cui YX, Kerby A, McDuff FK, Ye H, Turner SD. NPM-ALK inhibits the p53 120. Onofrillo C, Galbiati A, Montanaro L, Derenzini M. The pre-existing tumor suppressor pathway in an MDM2 and JNK-dependent manner. Blood. population of 5S rRNA effects p53 stabilization during ribosome biogenesis 2009;113(21):5217–27. inhibition. Oncotarget. 2017;8(3):4257–67. 145. Rassidakis GZ, Thomaides A, Wang S, Jiang Y, Fourtouna A, Lai R, et al. p53 121. Donati G, Bertoni S, Brighenti E, Vici M, Treré D, Volarevic S, et al. The gene mutations are uncommon but p53 is commonly expressed in balance between rRNA and ribosomal protein synthesis up- and anaplastic large-cell lymphoma. Leukemia. 2005;19(9):1663–9. downregulates the tumour suppressor p53 in mammalian cells. Oncogene. 146. Xu-Monette ZY, Møller MB, Tzankov A, Montes-Moreno S, Hu W, Manyam 2011;30(29):3274–88. GC, et al. MDM2 phenotypic and genotypic profiling, respective to TP53 122. Daftuar L, Zhu Y, Jacq X, Prives C. Ribosomal proteins RPL37, RPS15 and genetic status, in diffuse large B-cell lymphoma patients treated with RPS20 regulate the Mdm2-p53-MdmX network. PLoS One. 2013;8(7):e68667. rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;122(15):2630–40. 123. Spector DL, Ochs RL, Busch H. Silver staining, immunofluorescence, and immunoelectron microscopic localization of nucleolar phosphoproteins B23 147. Zenz T, Vollmer D, Trbusek M, Smardova J, Benner A, Soussi T, et al. TP53 and C23. Chromosoma. 1984;90(2):139–48. mutation profile in chronic lymphocytic leukemia: evidence for a disease 124. Biggiogera M, Fakan S, Kaufmann SH, Black A, Shaper JH, Busch H. specific profile from a comprehensive analysis of 268 mutations. Leukemia. Simultaneous immunoelectron microscopic visualization of protein B23 and 2010;24(12):2072–9. C23 distribution in the HeLa cell nucleolus. J Histochem Cytochem. 1989; 148. Zenz T, Kröber A, Scherer K, Häbe S, Bühler A, Benner A, et al. Monoallelic 37(9):1371–4. TP53 inactivation is associated with poor prognosis in chronic lymphocytic 125. Borer RA, Lehner CF, Eppenberger HM, Nigg EA. Major nucleolar proteins leukemia: results from a detailed genetic characterization with long-term shuttle between nucleus and cytoplasm. Cell. 1989;56(3):379–90. follow-up. Blood. 2008;112(8):3322–9. 126. Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nat 149. Guièze R, Robbe P, Clifford R, de Guibert S, Pereira B, Timbs A, et al. Rev Cancer. 2006;6(7):493–505. Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL. Blood. 2015;126(18):2110–7. 127. Lindström MS. NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling. Biochem Res Int. 2011;2011:195209. 150. Stengel A, Schnittger S, Weissmann S, Kuznia S, Kern W, Kohlmann A, et al. TP53 https://doi.org/10.1155/2011/195209. mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, 128. Lindström MS, Zhang Y. B23 and ARF: friends or foes? Cell Biochem Biophys. low hypodiploidy, and a poor prognosis. Blood. 2014;124(2):251–8. 2006;46(1):79–90. 151. Seifert H, Mohr B, Thiede C, Oelschlägel U, Schäkel U, Illmer T, et al. The 129. Colombo E, Alcalay M, Pelicci PG. Nucleophosmin and its complex network: prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid a possible therapeutic target in hematological diseases. Oncogene. 2011; leukemia. Leukemia. 2009;23(4):656–63. 30(23):2595–609. 152. Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, et al. 130. Itahana K, Bhat KP, Jin A, Itahana Y, Hawke D, Kobayashi R, et al. Tumor Mutational Spectrum, Copy Number Changes, and Outcome: Results of a suppressor ARF degrades B23, a nucleolar protein involved in ribosome Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin biogenesis and cell proliferation. Mol Cell. 2003;12(5):1151–64. Oncol. 2015;33(33):3911–20. 131. Szebeni A, Olson MO. Nucleolar protein B23 has molecular chaperone 153. Jardin F, Jais JP, Molina TJ, Parmentier F, Picquenot JM, Ruminy P, et al. activities. Protein Sci. 1999;8:905–12. Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene 132. Chan LW, Lin X, Yung G, Lui T, Chiu YM, Wang F, et al. Novel structural co- expression signature and a poor prognosis under R-CHOP treatment: a expression analysis linking the NPM1-associated ribosomal biogenesis GELA study. Blood. 2010;116(7):1092–104. network to chronic myelogenous leukemia. Sci Rep. 2015;5:10973. 154. Alhejaily A, Day AG, Feilotter HE, Baetz T, Lebrun DP. Inactivation of the 133. Derenzini M, Sirri V, Pession A, Trerè D, Roussel P, Ochs RL, et al. Quantitative CDKN2A tumor-suppressor gene by deletion or methylation is common at changes of the two major AgNOR proteins, nucleolin and protein B23, related diagnosis in follicular lymphoma and associated with poor clinical outcome. to stimulation of rDNA transcription. Exp Cell Res. 1995;219(1):276–82. Clin Cancer Res. 2014;20(6):1676–86. 134. Derenzini M, Sirri V, Trerè D, Ochs RL. The quantity of nucleolar proteins 155. Iacobucci I, Ferrari A, Lonetti A, Papayannidis C, Paoloni F, Trino S, et al. nucleolin and protein B23 is related to cell doubling time in human cancer CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute cells. Lab Invest. 1995;73(4):497–502. lymphoblastic leukemia patients. Clin Cancer Res. 2011;17(23):7413–23. 156. Mian M, Scandurra M, Chigrinova E, Shen Y, Inghirami G, Greiner TC, et al. 135. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Clinical and molecular characterization of diffuse large B-cell lymphomas GIMEMA Acute Leukemia Working Party. Cytoplasmic nucleophosmin in with 13q14. 3 deletion. Ann Oncol. 2012;23(3):729–35. acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005; 352(3):254–66. 157. Ouillette P, Collins R, Shakhan S, Li J, Li C, Shedden K, et al. The prognostic 136. Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid leukemia carrying significance of various 13q14 deletions in chronic lymphocytic leukemia. cytoplasmic/mutated nucleophosmin (NPMc_ AML): biologic and clinical Clin Cancer Res. 2011;17(21):6778–90. features. Blood. 2007;109(3):874–85. 158. Okamoto R, Ogawa S, Nowak D, Kawamata N, Akagi T, Kato M, et al. 137. The Cancer Genome Atlas Research Network. Genomic and Epigenomic Genomic profiling of adult acute lymphoblastic leukemia by single Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013; nucleotide polymorphism oligonucleotide microarray and comparison to 368:2059–74. pediatric acute lymphoblastic leukemia. Haematologica. 2010;95(9):1481–8. 138. Colombo E, Martinelli P, Zamponi R, Shing DC, Bonetti P, Luzi L, et al. 159. Scheijen B, Boer JM, Marke R, Tijchon E, van Ingen Schenau D, Waanders E, Delocalization and destabilization of the Arf tumor suppressor by the et al. Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia leukemia-associated NPM mutant. Cancer Res. 2006;66(6):3044–50. development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients. Haematologica. 2017;102(3):541–51. 139. Colombo E, Bonetti P, Lazzerini Denchi E, Martinelli P, Zamponi R, et al. Nucleophosmin is required for DNA integrity and p19Arf protein stability. 160. Cao B, Fang Z, Liao P, Zhou X, Xiong J, Zeng S, et al. Cancer-mutated Mol Cell Biol. 2005;25(20):8874–86. ribosome protein L22 (RPL22/eL22) suppresses cancer cell survival by 140. den Besten W, Kuo ML, Williams RT, Sherr CJ. Myeloid leukemia-associated blocking p53-MDM2 circuit. Oncotarget. 2017;8(53):90651–61. nucleophosmin mutants perturb p53-dependent and independent activities 161. Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, et al. ALK- of the Arf tumor suppressor protein. Cell Cycle. 2005;4(11):1593–8. anaplastic large-cell lymphoma is clinically and immunophenotypically Derenzini et al. Journal of Hematology & Oncology (2018) 11:75 Page 13 of 13 different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496–504. 162. Drygin D, O'Brien SE, Hannan RD, McArthur GA, Von Hoff DD. Targeting the nucleolus for cancer-specific activation of p53. Drug Discov Today. 2014; 19(3):259–65. 163. Quin JE, Devlin JR, Cameron D, Hannan KM, Pearson RB, Hannan RD. Targeting the nucleolus for cancer intervention. Biochim Biophys Acta. 2014; 1842(6):802–16. 164. Brighenti E, Treré D, Derenzini M. Targeted cancer therapy with ribosome biogenesis inhibitors: a real possibility? Oncotarget. 2015;6(36):38617–27. 165. Jin R, Zhou W. TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis. Biochim Biophys Acta. 2016;1866(2):189–96.
Journal of Hematology & Oncology – Springer Journals
Published: May 31, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera