Key Points• Richter syndrome has genomic complexity intermediate between chronic lymphocytic leukemia and diffuse large B-cell lymphoma.• Inactivation of TP53 and of CDKN2A is a main mechanism in the transformation to Richter syndrome.Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). Although RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the preexisting CLL, the mechanisms leading to RS have not been clarified. To better understand the pathogenesis of RS, we analyzed a series of cases including 59 RS, 28 CLL phase of RS, 315 CLL, and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell-cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL phase, being present in approximately one half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. Although RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL phase preceding RS had not a generalized increase in genomic complexity compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions. (Blood. 2013;122(15):2673-2682
BackgroundMyelodysplastic syndrome with isolated chromosome 5q deletion (5q- syndrome) is a clonal stem cell disorder characterized by ineffective hematopoiesis. MicroRNAs (miRNAs) are important regulators of hematopoiesis and their aberrant expression was detected in some clonal hematopoietic disorders. We thus analyzed miRNA expressions in bone marrow CD34+ cells of 5q- syndrome patients. Further, we studied gene expressions of miR-143, miR-145, miR-378 and miR-146a mapped within the 5q deletion.ResultsUsing microarrays we identified 21 differently expressed miRNAs in 5q- patients compared to controls. Especially, miR-34a was markedly overexpressed in 5q- patients, suggesting its role in an increased apoptosis of bone marrow progenitors. Out of four miRNAs at del(5q), only miR-378 and miR-146a showed reduced gene expression in the patients. An integrative analysis of mRNA profiles and predicted putative targets defined potential downstream targets of the deregulated miRNAs. The list of targets included several genes that play an important role in the regulation of hematopoiesis (e.g. KLF4, LEF1, SPI1).ConclusionsThe study demonstrates global overexpression of miRNAs is associated with 5q- phenotype. Identification of hematopoiesis-relevant target genes indicates that the deregulated miRNAs may be involved in the pathogenesis of 5q- syndrome by a modulation of these targets. The expression data on miRNAs at del(5q) suggest the presence of mechanisms for compensation of a gene dosage.
MicroRNAs (miRNAs) are small non-coding RNAs functioning as regulators of hematopoiesis. Their differential expression patterns have been linked with various pathological processes originating from hematopoietic stem cells (HSCs). However, limited information is available regarding the role of miRNAs in myelodysplastic syndrome (MDS). Using miRNA arrays, we measured expression of 1,145 miRNAs in CD34+ bone marrow cells obtained from 39 MDS and acute myeloid leukemia (AML) evolved from MDS patients, and compared them with those of six healthy donors. Differential miRNA expression was analyzed and a panel of upregulated (n¼13) and downregulated (n¼9) miRNAs were found (Po0.001) in MDS/AML patients. An increased expression of a large miRNA cluster mapped within the 14q32 locus was detected. Differences in miRNA expression of MDS subtypes showed a distinction between early and advanced MDS; an apparent dissimilarity was observed between RAEB-1 and RAEB-2 subtypes. In early MDS, we monitored upregulation of proapoptotic miR-34a, which may contribute to the increased apoptosis of HSCs. Patients with 5q deletion were characterized by decreased levels of miR-143* and miR-378 mapped within the commonly deleted region at 5q32. This is an early report describing differential expression in MDS CD34+ cells, likely reflecting their disease-specific regulation.
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