Differential Expression of MicroRNAs in CD34+ Cells of 5q- Syndrome

<p>Abstract</p> <p>Background</p> <p>Myelodysplastic 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 <it>miR-143</it>, <it>miR-145</it>, <it>miR-378 </it>and <it>miR-146a </it>mapped within the 5q deletion.</p> <p>Results</p> <p>Using microarrays we identified 21 differently expressed miRNAs in 5q- patients compared to controls. Especially, <it>miR-34a </it>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 <it>miR-378 </it>and <it>miR-146a </it>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. <it>KLF4</it>, <it>LEF1</it>, <it>SPI1</it>).</p> <p>Conclusions</p> <p>The 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.</p

Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia 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

Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia 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

Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter Syndrome

Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). While 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 pre-existing CLL, mechanisms leading to RS have not been clarified yet. 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 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. While 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 when compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions