TY - JOUR
AU - Phillips, Gordon L.
AB - Abstract The mechanisms underlying hematopoietic stem cell or progenitor cell abnormalities in myelodysplastic syndromes (MDSs) remain poorly characterized. Current evidence exists for multiple intrinsic and extrinsic influences upon the stem cell in these disorders. These influences are outlined in this review and include: stem cell characteristics in MDSs, as compared with those in acute myelogenous leukemia; the role of increased apoptosis; the role of signaling pathway abnormalities; the influences of immune modulation; and the effect of stromal cells and stromal cell cytokine production. Despite numerous studies that have examined these factors, how they converge to produce a situation in which accelerated proliferation and accelerated death occur simultaneously remains largely an unexplored area. It is anticipated that future studies that focus on well‐characterized and purified progenitor populations in these disorders will elucidate the process by which ineffective hematopoiesis results from the influences of stem cell abnormalities versus abnormalities in the stem cell's microenvironmental and immunologic milieu. Myelodysplasia, Progenitor cells, Apoptosis Stem Cell Characterization in Myelodysplastic Syndromes The myelodysplastic syndromes (MDSs) are a group of hematologic disorders often characterized by cytopenias in one or more hematopoietic lineages despite marrows that demonstrate hypercellularity and evidence for ineffective and dyspoietic hematopoiesis. Patients with these disorders experience complications from cytopenias and may have progression to acute leukemia [1]. Myelodysplasia is classified into the categories of refractory anemia (RA), RA with ringed sideroblasts (RARS), and RA with excess blasts (RAEB) [1]. While there may be an increase in immature precursors in the marrow, there is often an absence of blast cell accumulation such as that seen in acute myelogenous leukemia (AML). Like AML, MDS is considered a clonal stem cell disorder. While multipotential precursor/stem cells in AML have been characterized based on immunophenotype and expression of other signaling pathway mediators, little information is available for the MDS counterpart in terms of immunophenotype or comparison to normal or AML hematopoietic stem cells. In AML, the stem cell has certain conserved features that are unique to the leukemic stem/progenitor cell and not found in normal hematopoietic stem cells [2,3]. These include lack of expression of CD90 and CD117; expression of CD123, interferon regulatory factor 1 (IRF‐1), and death‐associated protein kinase [4]; and constitutive activation of NF‐κB [3–7]. Whether such unique features are shared by early MDS stem/progenitors has not yet been elucidated. Such characterization will be important, since currently there is little consensus as to which cell type should be examined as an MDS “stem” cell. The best prototype at present is CD34+ cells possessing a clonal marker. Whether a truly multipotential stem/progenitor cell is actually involved in MDSs also remains controversial. In some patients with the 5q‐ syndrome, for example, deletions occur in hematopoietic stem cells with a combined lymphomyeloid potential, and cells in the CD34+CD38−, as well as in the CD34+CD19+, compartments can express the deletion [8]. Controversy continues to exist about involvement of nonmyeloid lineages in MDSs, with some cases demonstrating T‐cell, B‐cell, or natural killer–cell involvement as assessed by aberrant chromosome presence in these populations, whereas in other cases, this has not been found [9–12]. Increased apoptosis in bone marrow B lymphocytes, but not T lymphocytes, has been noted in MDSs [13], but whether this represents B‐cell precursor involvement or a secondary event has not been worked out. In AML, blasts within individual patients are heterogeneous in their surface antigen expression and proliferative ability [7]. Subsequent to transformation, differentiation occurs, creating a hierarchy of progenitors in AML. The so‐called AML initiating cells vary in their proliferative capacity. The frequency of colony‐forming units (CFUs), both initially and after 2–4 weeks of culture in liquid medium, has been found to vary over 4 logs among individual AML patients [7]. Whether individual CD34+ cells or CD34+ cell subsets possessing long‐term culture‐initiating capacity in MDSs vary in their proliferative potential to this degree has not been reported, nor has it been determined that these cells can initiate human pathology in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice as can the AML‐initiating cells. In NOD/SCID mice transplanted with marrow from patients with MDSs, long‐term propagation of normal, but not clonal, human progenitors has been noted [14]. At the genomic level, MDS is characterized by certain chromosomal translocations and deletions that can be found by routine cytogenetics in about 50% of patients [15]. When detailed microsatellite allelotypes are examined in MDS patients, a high percentage of loss of heterozygosity is identified on chromosome 5q, 7q, 17p, or 20q, all common cytogenetic abnormalities seen in MDSs. Furthermore, loss of heterozygosity is noted on chromosomes 1p, 1q, and 18q, suggesting that these chromosomes might also contain novel tumor suppressor genes [16]. Loss of heterozygosity may also increase with disease progression [17]. Emergence of mutations in transcription factors has also been found to be associated with evolution toward MDSs but is usually not found in de novo MDSs [18]. There is also evidence for epigenetic alterations in MDSs. Aberrant p15 gene promoter methylation in therapy‐related MDSs has been observed, and this is thought to be an early event in evolution of some patients to AML [19,20]. Methylation of p15 has been associated with deletion or loss of chromosome 7q [21]. Hypermethylation of p15 is noted in about one third of MDS cases and may be associated with disease progression [22], and it has been noted that p15 methylation may contribute to defective megakaryocytopoiesis often seen in MDSs [23]. There are few data regarding quantitation of CD34+ cells in MDSs, as compared with those in normal or AML marrow. A high CD34+ cell count of > 1 × 106/L has been found to be a poor prognostic factor in MDSs, however [24]. Increased numbers of circulating colony‐forming cells have been noted in advanced stages of MDSs such as RAEB and RAEB in transformation (REAB‐T) [25]. Some CD34+ cells from MDS patients may have reduced expression of granulocyte colony‐stimulating factor (G‐CSF) receptor, as compared with normal CD34+ cells, and this correlates with incidence of neutropenia [26]. The degree of expression of the Wilms' tumor gene (WT1), a tumor suppressor gene coding for a zinc‐finger transcription factor located on chromosome 11p13, has been found to increase as MDS advances, but this has been analyzed only in unseparated cell populations [27]. Lung resistance protein expression was found to be more frequently expressed in MDS than in de novo AML, but this was only partially correlated with P‐glycoprotein expression, and which cells expressed this protein was not determined [28]. When CD34+ cells from MDS patients are compared with normal CD34+ cells using high‐density oligonucleotide microarray analysis, using an expression profile of 11 genes, patients with low‐risk disease could be separated from patients with high‐risk MDS, and both groups could be separated from the control group [29]. Genes that were downregulated in MDS included the retinoic acid–induced gene (RAI2); the radiation‐inducible, immediate early‐response gene (IEX1); and the stress‐induced phosphoprotein 1. All of these are so‐called defensive proteins, suggesting that MDS CD34+ cells may accumulate defects that prevent normal hematopoiesis [29]. AC133 cells from patients with MDSs have been found to express the gene encoding Delta‐like (Dlk), whereas this is not expressed in AML [30]. Shortened telomeres and high telomerase activity almost always correlate with disease severity in MDSs [31]. There is a paucity of reports on the telomere length in CD34+ cells from MDS patients, however, as most studies have used extracts from whole marrow populations. There is also evidence that chromosomal instability and DNA repair defects may be involved in the progression of MDSs [32]. X‐ray–induced micronuclei were increased in MDS patient samples, as compared with those from normal individuals, and the expression levels of nucleotide excision repair (NER) genes in peripheral blood mononuclear cells from high‐risk MDS patients were reduced, as compared with those in low‐risk patients [32]. Microarray analysis with AC133+ cells from MDS patients has shown expression of PIASy in the indolent stages of MDSs, with decrease in the more advanced stages [33]. This gene, which catalyses protein modification with ubiquitin‐like agents, induces apoptosis when introduced into a mouse myeloid cell line. Some patients with MDSs do have residual polyclonal stem cells remaining, as evidenced by the ability of some patients to enter a complete remission and undergo autologous stem cell transplantation with cytogenetically normal CD34+ cells [34]. In one pilot study of intensive chemotherapy for poor‐prognosis MDS/AML patients, 7 of 8 with cytogenetic abnormalities regained cytogenetically normal bone marrow, and some have demonstrated prolonged polyclonal remissions after intensive combination chemotherapy as assessed by polymerase chain reaction (PCR), human androgen receptor gene assay, and X‐chromosome inactivation patterns [35]. Role of Increased Apoptosis While there is evidence that both MDS and AML may arise from transformation at the level of the pluripotent hematopoietic stem cell [10], MDSs can be distinguished from AML morphologically and on the basis of percentage of blasts, and it has been demonstrated that apoptotic activity may be the dominant feature in MDSs, which distinguishes it from AML. Apoptosis in marrow cells is increased in MDSs, as compared with normal subjects, but whether this involves the earliest stem cells or later progenitor/precursor cells remains to be determined. In one study of 54 patients with MDS, 30 with early and 24 with later stages of disease, TUNEL (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling) and annexin V assays revealed that the patients with early‐stage disease had increased apoptosis, compared with those in later stages of disease [36]. Caspase 3 activity was increased in early‐stage MDS patients versus those with excess blasts in later phases of the disease. Inhibition of caspase activation decreased annexin V–positive cells but did not result in enhanced colony formation in vitro [36]. In another study, 51 cases of MDSs were analyzed for apoptosis incidence by TUNEL assay. The apoptotic rate in MDS patients was 5.5% versus 0.6% in normals and 0.4% in AML. The percentage of CD34+ cells was also higher in patients with AML and in the MDS subtypes RAEB, RAEB‐T, and chronic myeloid myocytic leukemia (CMML) than in control subjects and patients with RA. Poor prognosis was correlated with higher apoptotic rates [37]. Patients with 5q‐ syndrome have been found to have less apoptosis than patients from other MDS subtypes [38]. In some MDS patients, increased apoptosis has been noted in both early and mature hematopoietic cells as based on annexin V expression [39]. Greater loss of mitochondrial potential has also been found in MDSs, and these findings span RA, RARS, RAEB (types 1 and 2), and RAEB‐T [39]. Using a double‐labeling technique that combines the TUNEL method with immunocytochemistry for the CD34 antigen, it was found that the apoptotic rate appeared higher in CD34 negative than in positive cells [40]. No difference in apoptotic rate was observed between normal and MDS CD34+ cells. Greater caspase 3 activity was also seen in MDSs than in AML, and bromodeoxyuridine incorporation and ability to differentiate were also higher in MDSs than in AML. Those patients with the highest percentage of apoptosis were the least likely to respond to any therapy [40]. These nonresponders also had higher levels of β2‐microglobulin, interleukin‐6 (IL‐6), tumor necrosis factor alpha (TNF‐α), IL‐1β, and IL‐1 receptor antagonist (IL‐1ra) in serum. Apoptosis in CD34+ cells has also been associated with intracellular redox changes in conjunction with elevated TNF‐α[41]. Another report found that proliferation rates in marrow cells from MDSs and CMML were high, as measured by proliferating cell nuclear antigen and bromodeoxyuridine incorporation [42]. Apoptosis was also highest in MDSs and CMML, as measured by annexin V and caspase 3 activity. No significant difference in proliferation in CD34+ cells was found from various leukemias or MDSs, as measured by bromodeoxyuridine incorporation [43]. Other groups have also presented evidence that increased apoptosis in early stages may decrease as the disease moves toward the leukemic stages [44], and another group that evaluated annexin V, Ki67, and Bcl‐2 expression by flow cytometry in 102 patients and 30 normal subjects found that apoptosis was increased in RA/RARS and RAEB, as compared with that seen in normal marrow. The rate of apoptosis and Bax/BAD: Bcl‐2/Bcl‐X ratio inversely correlated with the International Prognostic Index and cytogenetics, suggesting that in those cases with higher rates of apoptosis, prognosis was better [45]. In another study of marrow mononuclear cells from 168 MDS samples, Bcl‐2 and Bcl‐xL expression was higher in RAEB and RAEB‐T than in CMML, whereas proapoptotic proteins Bad, Bax, and Bcl‐xS were more highly expressed in RA and RARS [46]. Early disease was associated with excessive apoptosis and elevated ratios of apoptosis to proliferation. It was suggested that leukemic transformation arises through inhibition of apoptosis rather than by excessive cell growth [47]. During culture of marrow from RARS patients, higher spontaneous apoptosis and caspase activity was demonstrated than in marrow cells from healthy donors. Fas ligation increased apoptosis and decreased colony growth equally in RARS and controls but caused more caspase activation in RARS. Caspase inhibition reduced apoptosis, increased proliferation, and enhanced erythroid colony growth from CD34+ cells in RARS but showed no effect on normal cells [48]. G‐CSF has been found to significantly reduce Fas‐mediated caspase‐3 activity in marrow from RARS patients. G‐CSF resulted in increased erythroid colony formation in CD34+ cells from RARS patients, whereas in normal marrow, the number of erythroid colonies decreased [49]. Almost 50% of erythroid progenitor cells derived from patients with MDSs exhibit spontaneous release of cytochrome c from mitochondria with ensuing activation of caspase‐9. G‐CSF has been found to inhibit cytochrome c release and apoptosis [50]. Mutations of mitochondrial DNA may impair iron metabolism and heme synthesis through prevention of iron reduction for use by ferrochelatase in addition to enhancement of apoptosis [51]. Role of TNF TRAIL, the TNF‐related apoptosis‐inducing ligand, reduces the number of myeloid colonies (colony‐forming units–granulocyte macrophages [CFU‐GMs] and clusters) from patients with AML, CML, and MDSs. No negative effects on the number of CFU‐GMs from normal subjects were noted [52]. In RA, enhanced signaling through the TNFRI‐TRADD (TNF receptor–associated death domain protein)–FADD (Fas‐associated death domain protein ) pathway has been observed [53]. Due to the observations that TNF may play a major role in apoptotic death of marrow cells in MDSs [54], clinical trials of TNF inhibitors have been conducted in MDSs. Infliximab, an anti‐TNF monoclonal antibody, has been demonstrated to result in sustained erythroid responses in patients and to decrease the percentage of apoptotic stem cells in the marrow [55]. Responses to other agents that decrease TNF levels, such as the combination of oral ciprofloxacin, pentoxifylline, and dexamethasone, have also been found to correlate with the intensity of cell apoptosis [56]. Another study with soluble TNF receptor (TNFR:Fc) demonstrated no responses in 10 patients with cytopenic MDS [57]. Thus, while there is evidence for a role of TNF‐α in apoptosis induction in MDSs, the clinical effects of TNF inhibition in MDSs remain controversial. Summary of Apoptosis Effects Reports have consistently shown increased rates of apoptosis in MDS marrows. This no doubt plays a role in the ineffective erythropoiesis that is a hallmark of the RA and RARS subtypes of MDSs. The degree of apoptosis appears to decrease as MDS evolves to AML. What remains less clear, however, is the role of apoptosis in the early stem or progenitor cell and which of many apoptotic mediators play a role in this process (Table 1). While some studies have shown increased apoptosis in early progenitor cells, the role that this plays in the pathobiology of MDS is uncertain as differentiation along multiple lineages occurs, accounting for the hypercellularity usually noted in MDS marrows. In any case, if apoptosis pathways are active in early MDS progenitors, the tendency for proliferation must have ascendancy due to the tendency for clonal maintenance and, in some cases, dominance. Which molecular changes lead to a decline in later progenitor apoptosis and loss of maturation ability in the transformation to AML remain uncertain but may be elucidated by future genomic or proteonomic analysis of highly selected progenitor cells (Table 2). Table 1. Apoptosis mediators in myelodysplasia Fas/Fas ligand via FADD (Fas‐associated death domain protein) Bcl‐2 Mitochondrial cytochrome c release PIASy Survivin and IAPs (inhibitors of apoptosis) TNF via TRADD (TNF receptor–associated death domain protein) Caspase activation via any of the above mechanisms Fas/Fas ligand via FADD (Fas‐associated death domain protein) Bcl‐2 Mitochondrial cytochrome c release PIASy Survivin and IAPs (inhibitors of apoptosis) TNF via TRADD (TNF receptor–associated death domain protein) Caspase activation via any of the above mechanisms Abbreviation: TNF, tumor necrosis factor. Open in new tab Table 1. Apoptosis mediators in myelodysplasia Fas/Fas ligand via FADD (Fas‐associated death domain protein) Bcl‐2 Mitochondrial cytochrome c release PIASy Survivin and IAPs (inhibitors of apoptosis) TNF via TRADD (TNF receptor–associated death domain protein) Caspase activation via any of the above mechanisms Fas/Fas ligand via FADD (Fas‐associated death domain protein) Bcl‐2 Mitochondrial cytochrome c release PIASy Survivin and IAPs (inhibitors of apoptosis) TNF via TRADD (TNF receptor–associated death domain protein) Caspase activation via any of the above mechanisms Abbreviation: TNF, tumor necrosis factor. Open in new tab Table 2. Possible changes involved in myelodysplastic syndromes (MDSs) to acute myelogenous leukemia transformation Further chromosomal aberrations or transcription factor changes Epigenetic changes such as p15INK4b Increased WT expression Shortened telomere/high telomerase activity Possible changes in apoptosis and cell cycle mediatorsa (e.g., increased Bcl‐2 expression) Further chromosomal aberrations or transcription factor changes Epigenetic changes such as p15INK4b Increased WT expression Shortened telomere/high telomerase activity Possible changes in apoptosis and cell cycle mediatorsa (e.g., increased Bcl‐2 expression) aSee Table 1 for a list of apoptosis mediators that have been examined in MDSs. Open in new tab Table 2. Possible changes involved in myelodysplastic syndromes (MDSs) to acute myelogenous leukemia transformation Further chromosomal aberrations or transcription factor changes Epigenetic changes such as p15INK4b Increased WT expression Shortened telomere/high telomerase activity Possible changes in apoptosis and cell cycle mediatorsa (e.g., increased Bcl‐2 expression) Further chromosomal aberrations or transcription factor changes Epigenetic changes such as p15INK4b Increased WT expression Shortened telomere/high telomerase activity Possible changes in apoptosis and cell cycle mediatorsa (e.g., increased Bcl‐2 expression) aSee Table 1 for a list of apoptosis mediators that have been examined in MDSs. Open in new tab Role of Signaling Abnormalities The receptor tyrosine kinase, TEK/Tie‐2, is expressed by primitive hematopoeitic stem cells [58]. By PCR and Northern analysis, increased expression of TEK and its ligand was seen in 11/17 cases of acute and chronic myeloid leukemia [58]. Expression of this receptor/ligand pair has not been well described in MDSs, however. The degradation of several intracellular proteins involved in cell cycle control and tumor growth is regulated by the ubiquitin‐dependent multicatalytic proteasome complex (proteasome). Leukemic cells are more susceptible and are killed by apoptosis in the presence of proteasome inhibition [59]. Poly (adenosine diphosphate–ribose) polymerase cleavage was noted to be involved in this process. Constitutive activation of ERK‐1/2 and MEK‐1/2 has been observed in AML [60]. Whether such activation occurs in MDSs is uncertain. Low molecular–weight GTP‐binding proteins, such as Ras, participate in growth control, differentiation, cytoskeletal organization, and cytokine‐ and chemoattractant‐induced signaling events. In MDSs, Ras activation may occur by point mutations, overexpression, or alteration of NF‐κ B‐Ras‐GTPase activation proteins. Approximately 15% of MDS cases express mutated Ras [61]. These are postinitiation events in the genesis of leukemia, but they may also modulate growth factor–dependent and–independent growth potential of myelodysplastic progenitors [62]. Megakaryocytic differentiation has been found defective in MDSs. This is postulated to be related to deregulated thrombopoietin receptor (c‐mpl)–mediated signaling pathways [63]. STAT 3 and 5, as well as ERK‐1 and ‐2, were found to be activated. C‐mpl expression was normal. STAT 3 and STAT 5 activation may contribute to the malignant phenotype of the dysplastic cells [63]. The erythroid lineage also demonstrates abnormalities in signal transduction pathways. In response to stimuli such as erythropoietin, erythroid progenitors show abnormal phosphorylation of STAT 5 and abnormal expression of GATA‐1 [64]. Abnormal signaling pathway mediation is therefore present in early MDS progenitors and in more differentiated progenitors, but whether this is primary or secondary and how these contribute to the lack of normal precursor maturation and increased apoptosis and possible evolution to leukemia remain largely unknown. Effect of Immune Modulation on MDS Progenitor Cells There is some indication that T lymphocytes may inhibit hematopoiesis in MDSs. Antithymocyte globulin (ATG) has been found to inhibit hematopoietic progenitor cells at high concentrations. At lower concentrations, however, increased colony growth with normal, MDS, and aplastic anemia marrow CD34+ cells has been observed [65]. The clinical responses noted with ATG and cyclosporine A suggest that T cell–mediated immunological modulation of intrinsic stem cell defects may occur in MDSs. When T‐cell repertoires of MDS patients are examined before and after ATG by T‐cell receptor–Vbeta (TCR‐Vbeta) spectra type analysis, skewing is seen pretreatment, and in some patients who recover normal blood counts, skewing is lost at 3 to 6 months after treatment. Sequencing of DNA from the complementarity‐determining regions of TCR‐Vbeta confirmed clonal T‐cell dominance in some cases. The T cells are CD3+/CD45RA+/HLA‐DR negative [66]. A nonclonal X‐chromosome inactivation pattern was associated with a response to ATG. This was attributed to incomplete clonal expansion, with ATG allowing emergence of normal hematopoiesis by decreasing the immunological suppression on normal progenitors [67]. HLA‐DR15 expression has also been reported to correlate with treatment responses to immunosuppressive medications in MDSs [68]. In MDSs with trisomy 8, the number of Fas‐expressing CD34+ cells was found to be increased, and activated cas‐pase‐3 was increased compared with normal cells. Fas antagonist was able to expand cells from cases with trisomy 8 but not from cases with other cytogenetic abnormalities, and Fas receptor activation decreased the percentage of cells with trisomy 8 [69]. Trisomy 8 progenitor cells were found to be inhibited by autologous CD8+V‐Beta–restricted T cells [70]. Qualitative and quantitative abnormalities in lymphoid and myeloid dendritic cells have also been found in MDSs [71]. There is, therefore, evidence that in some cases of MDSs, immunologic mechanisms involving both B‐ and T‐lymphocyte regulation are operative. The inhibitory T‐cell effect is substantiated by improvement in blood counts in some patients treated with ATG and cyclosporine [72]. As mentioned previously, whether the B‐ and T‐cell lineages are part of the MDS clone has been controversial [73], and thus immunologic aberrations may be only a secondary phenomenon in MDSs. Effect of Stroma and Cytokines on Progenitor Cells in MDSS Whether the hematopoietic microenvironment in myelodysplasia is normal has been a subject of debate; in any case, how the microenvironment influences stem cells or progenitor cells in MDSs is also incompletely understood. The ability of marrow stromal layers from normal subjects and patients with myelodysplasia to alter proliferation and survival of a GM‐CSF–and IL‐3–dependent cell line F‐36P has been compared. Augmented apoptosis was seen in 8/9 cultures with MDS stroma, as compared with normal stroma. No correlation with apoptosis and TNF concentration was noted, and the Fas/FasL system did not seem to be involved. Close cellular contact was required for this effect on apoptosis to occur [74]. Others have also found abnormalities of adherent layers in MDSs. In long‐term cultures, progenitors were detected for a median of 3.5 weeks in cultures from MDS marrow, compared with 18 weeks in cultures of normal marrow. IL‐1β expression in cultures generated from normals, but not MDS patients, declined between weeks 5 and 10 [75]. In contrast, others have reported that when biopsies of MDS marrow are used for stromal support, normal hematopoiesis is well supported for up to 12 weeks. Subtype classification and cytogenetics had no bearing upon this. The cultures were morphologically and functionally normal [76]. It has been found that cytokine secretion of IL‐6 and TNF‐α is increased in adherent layers from MDS patients versus normal subjects. The TNF appears to arise from macrophage components and the IL‐6 from fibroblast components. Both macrophages and fibroblasts had an increased apoptotic index [77]. TGF‐β has also been found to have inhibitory effects in MDSs [78]. The expression of various angiogenesis mediators has also been found to be altered in MDS marrows as compared with normal donor marrow. Blood levels of angiogenin and vascular endothelial growth factor (VEGF) have been found to be elevated in MDSs and in acute myeloid leukemia [79]. In marrow from normal subjects, low‐intensity VEGF expression was found in myeloid elements. In CMML, intense expression of the VEGF receptors Flt‐1 or KDR, or both, were found. AML and MDS marrows also had VEGF expression, and the abnormally localized immature myeloid precursors coexpressed VEGF and Flt receptors, suggesting autocrine cytokine interaction [80]. Neutralization of VEGF suppressed generation of TNF‐α and IL‐1β from MDS cells and promoted the formation of CFU–granulocyte‐erythroid‐macrophage megakaryocyte and BFU‐E [81]. The role of abnormal stromal cytokine expression and of increased angiogenesis in MDSs has led to trials of agents that have potential to modulate these. These agents include anti‐VEGF antibodies, thalidomide, thalidomide derivatives (IMiDs), and amifostine. The cytoprotectant, amifostine, has been found to stimulate stem cells in MDSs [81] and to improve growth of CFU‐GM and BFU‐Es [82], but whether amifostine acts directly or through expression of stromal cell–generated cytokines or via antioxidant effects remains unclear. Clinical responses to amifostine in the form of decreased transfusion requirements have been reported, but response rates are low and duration short [83]. Summary It has been hypothesized that the pathogenesis of MDSs may lie in a targeted injury to or mutations within multipotential hematopoietic stem cells that are followed by immunologic responses that adversely affect progenitor survival (Fig. 1) [84]. This results in accelerated proliferation and premature death of marrow cells amplified by apoptosis‐inducing cytokines such as TNF‐α and Fas ligand. In MDSs, many proinflammatory cytokines have elevated expression, and whether this is a primary or subsequent phenomenon is uncertain. In MDS marrows, cells demonstrate impaired differentiation and increased propensity to apoptosis, but as the disease progresses, increased proliferation and decreased apoptosis occur, and progression to AML can occur. Figure 1. Open in new tabDownload slide Influences on the myelodysplastic syndrome (MDS) clone that lead to the dual presence of increased proliferation and ineffective hematopoiesis manifested as apoptosis in this group of marrow disorders with complex pathogenesis. Figure 1. Open in new tabDownload slide Influences on the myelodysplastic syndrome (MDS) clone that lead to the dual presence of increased proliferation and ineffective hematopoiesis manifested as apoptosis in this group of marrow disorders with complex pathogenesis. The observations that intrinsic progenitor abnormalities, epigenetic modifications, abnormal apoptosis tendency, abnormal signal transduction responses, and abnormal micro‐environmental and immunologic influences all contribute to MDS pathogenesis elucidate the challenges in treating such a disease. The paradox of simultaneous increased proliferation and apoptosis suggests that antiproliferative and apoptotis‐inhibiting therapies may need to be used in conjunction, as apoptosis‐inhibiting therapies, such as thalidomide or IMiDs, might actually have a protective effect on the earliest progenitors with a proliferative advantage. Antiproliferative therapies would only serve to worsen cytopenias unless they are of sufficient intensity to allow re‐emergence of normal hematopoiesis. Thus far, only autologous or allogeneic stem cell transplants have achieved this. Since it appears that most microenvironmental and immunologic abnormalities seen in the disorder are secondary phenomena, treatments directed at abnormal cytokine production or immune modulatory treatments are unlikely in the majority of cases to eliminate the MDS clone, although in some cases, durable clinical improvements have been noted. This makes it important to understand abnormalities in the MDS stem cell itself if nontransplant therapies are to have significant impact in this disorder. Alterations of the stem cell in MDSs are currently not adequately characterized. Most studies in MDSs have not isolated CD34+ cells but have simply reported on whole mononuclear marrow cell fractions. Given the heterogeneity of marrow cells, this approach is unlikely to give meaningful information about alterations in stem cells or early progenitor cells in myelodysplasia. In the future, it will be important to be able to distinguish MDS stem cells from normal and AML stem cells in order to fully exploit treatment options with targeted therapies, immune modulators, or antiapoptotic agents. Microarray analysis and ability to analyze activation of signal pathways and apoptosis at single cell levels should now make these types of studies timely and feasible. Serial studies in individual patients will also be of importance to understand genetic and epigenetic changes at the earliest stem/progenitor cell level in these patients. Data are emerging to suggest that gene expression profiles on light‐density marrow can predict which MDS patients will progress to AML [85]. These studies will allow dissection of stem cell defects from alterations in the microenvironmental and immunologic milieu, all of which may contribute to the syndromes manifested as myelodysplasia. 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TI - The Hematopoietic Stem Cell in Myelodysplasia
JF - Stem Cells
DO - 10.1634/stemcells.22-4-590
DA - 2004-07-01
UR - https://www.deepdyve.com/lp/oxford-university-press/the-hematopoietic-stem-cell-in-myelodysplasia-p0yj43zGxl
SP - 590
EP - 599
VL - 22
IS - 4
DP - DeepDyve
ER -