British Journal of Haematology

Wong, K. F.

doi: 10.1111/j.1365-2141.2009.08049.xpmid: 20064161

Nakayama‐Ichiyama, Shoko; Yokote, Taiji; Oka, Satoko; Takubo, Takayuki; Tsuji, Motomu; Hanafusa, Toshiaki

doi: 10.1111/j.1365-2141.2009.08050.xpmid: 20085576

Yaccoby, Shmuel

doi: 10.1111/j.1365-2141.2010.08141.xpmid: 20230410

Advances in multiple myeloma support the notion that the associated bone disease, characterized by increased osteoclastogenesis and suppressed osteoblastogenesis, is both a consequence and necessity of tumour progression. Osteoblastogenesis is suppressed by secreted inhibitors and dysregulation of cell‐surface ‘coupling’ factors on osteogenic cells. Osteoclastogenesis is increased as a consequence of osteoblast deactivation and of production of osteoclast‐activating factors. Osteoclasts express soluble and cell‐surface factors that stimulate myeloma growth, while osteoblasts produce bone‐building factors that restrain growth of myeloma cells that are dependent on the microenvironment; detailed molecular mechanisms are discussed. Experimental and clinical findings indicate that pharmacological and experimental osteoblast‐activating agents that effectively promote bone formation also reduce growth of myeloma cells within bone, seemingly by simultaneously stimulating osteoblastogenesis and restraining osteoclastogenesis. Unravelling mechanisms of myeloma bone disease expands horizons for developing novel interventions and also facilitates better understanding of the association between induction of osteolysis and disease progression.

Cuijpers, Maria L. H.; Raymakers, Reinier A. P.; MacKenzie, Marius A.; De Witte, Theo J. M.; Swinkels, Dorine W.

doi: 10.1111/j.1365-2141.2009.08051.xpmid: 20067561

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal haematopoietic stem cell malignancies. A subgroup, the so‐called sideroblastic MDS, shows ring sideroblasts in the bone marrow aspirate that represent mitochondrial iron accumulation. Patients with sideroblastic MDS also develop systemic iron overload and generally have a low‐risk MDS. Therefore it is important to understand the mechanisms responsible for iron accumulation and the associated toxicity in these patients. Recently, low levels of the iron‐regulatory peptide hepcidin were found to contribute to body iron overload in β‐thalassaemia patients. A similar mechanism may account for systemic iron accumulation in sideroblastic MDS. Mitochondrial iron accumulation is observed in several subtypes of MDS, and predominantly in refractory anaemia with ring sideroblasts. The presence of ring sideroblasts is also the diagnostic hallmark in patients with inherited forms of sideroblastic anaemia. The ever‐increasing insights into the affected pathways in inherited sideroblastic anaemia may lead to a better comprehension of the pathogenesis of mitochondrial iron accumulation in MDS patients. Overall, an improved understanding of the mechanisms responsible for iron overload in MDS will lead to novel treatment strategies to reduce both systemic and mitochondrial iron overload, resulting in less tissue damage and more effective erythropoiesis.

Raja, Karthick R. M.; Kovarova, Lucie; Hajek, Roman

doi: 10.1111/j.1365-2141.2010.08121.xpmid: 20201947

Flow cytometric immunophenotyping is considered an indispensable tool for the diagnosis, classification and monitoring of disease in monoclonal gammopathies. The clinical sensitivity of flow cytometry is comparable with advanced molecular methods. Clinical application of flow cytometry in monoclonal gammopathies has various dimensions, such as differential diagnosis of malignant plasma cell disorder from reactive plasmacytosis, identifying the progression risk in monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic multiple myeloma (MM), and minimal residual disease detection. Flow cytometry‐based clonality assessment with immunophenotyping encourages and enables the most stringent method of diagnosis and follow‐up. The objective of this review is to update the malignant plasma cells phenotypic profile of MGUS and MM. The most comprehensive antigens, such as CD19, CD27, CD28, CD45, CD56 and CD117, play a significant role in the characterization of normal and malignant plasma cells. Several research groups described the putative phenotype of myeloma cell progenitors, but no remarkable suggestion could be made because of disparity. This review also focuses on the association of malignant phenotypic markers and chromosomal aberrations that identify the specific prognostic features in monoclonal gammopathies.

Harrison, Claire N.; Bareford, David; Butt, Nauman; Campbell, Peter; Conneally, Eibhlean; Drummond, Mark; Erber, Wendy; Everington, Tamara; Green, Anthony R.; Hall, Georgina W.; Hunt, Beverley J.; Ludlam, Christopher A.; Murrin, Richard; Nelson‐Piercy, Catherine;

Amadori, Sergio; Suciu, Stefan; Selleslag, Dominik; Stasi, Roberto; Alimena, Giuliana; Baila, Liliana; Rizzoli, Vittorio; Borlenghi, Erika; Gaidano, Gianluca; Magro, Domenico; Torelli, Giuseppe; Muus, Petra; Venditti, Adriano;

Del Poeta, Giovanni; Ammatuna, Emanuele; Lavorgna, Serena; Capelli, Giovanni; Zaza, Serena; Luciano, Fabrizio; Ottone, Tiziana; Del Principe, Maria Ilaria; Buccisano, Francesco; Maurillo, Luca; Panetta, Paola; De Fabritiis, Paolo; Stasi, Roberto; Venditti, Adriano;

Flynn, Joseph M.; Andritsos, Leslie; Lucas, David; Byrd, John C.

doi: 10.1111/j.1365-2141.2010.08110.xpmid: 20230400

Second primary malignancies have long been associated with chronic lymphocytic leukaemia (CLL). We assessed secondary tumour samples from CLL and control patients for the presence of human papilloma virus (HPV). 132 CLL patients with 44 second malignancies were compared to a matched randomly‐identified control population of 264 non‐CLL patients with 54 solid malignancies. Polymerase chain reaction was performed with the highly conserved MY09/MY11 HPV primer. None of control samples were HPV‐positive, while 53% of samples from the CLL group were positive. This report describes preliminary evidence for the presence of HPV in secondary malignancies, in patients with CLL.

Sharawat, Surender K.; Bakhshi, Radhika; Vishnubhatla, Sreenivas; Bakhshi, Sameer

doi: 10.1111/j.1365-2141.2010.08084.xpmid: 20230407

The D‐Loop region of mitochondrial DNA (mtDNA) is the regulatory region for its replication and transcription. There are two hypervariable regions (HV‐I, HV‐II) and the rate of mutation in these regions is 100‐ to 200‐fold that of nuclear DNA. In the current study, the entire D‐loop region of mtDNA was amplified in two overlapping polymerase chain reaction fragments and variations were evaluated in 44 paediatric acute myeloid leukaemia (AML) patients by direct DNA sequencing methods. Median age of the patients was 8·5 years (1–18 years) and the male:female ratio was 3·8:1. A total of 222 variations were observed at 118 positions in the D‐Loop of 35/44 (79·5%) AML patients. The most common variations were T→C (24·6%) and C→T (21·4%) followed by A→G (15·8%). There was no significant difference in the event‐free survival (EFS) of patients with or without any variations (P = 0·40). Three variations in HV‐I, namely 16126T→C (P = 0·05), 16224T→C (P < 0·01) and 16311T→C (P < 0·001), were significantly associated with inferior EFS. In conclusion, this is the largest study to show a high frequency of mtDNA variations in paediatric AML and their potential relevance as a prognostic marker in this disease.