miRNA analysis in B‐cell chronic lymphocytic leukaemia: proliferation centres characterized by low miR‐150 and high BIC/miR‐155 expression

Abstract

Several miRNAs have been reported to be associated with immunoglobulin heavy chain (IgH) mutation and ZAP-70 expression status in blood samples of B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma (B-CLL/SLL). In the bone marrow and lymphoid tissues, proliferation centres (PCs) represent an important site of activation and proliferation of the neoplastic cells, suggesting that these tissues better reflect the biology of CLL than circulating blood cells. We collected 33 lymph nodes and 37 blood CLL samples and analysed IgH mutation status and ZAP-70 expression status. Expression of 15 miRNAs was analysed by qRT-PCR and RNA-ISH. Sixty-three per cent of the lymph node cases contained mutated IgH genes and 49% of the lymph node cases were ZAP-70-positive, and a significant correlation was observed between ZAP-70 expression and IgH mutation status. Of the blood CLL samples, 49% contained mutated IgH sequences. The miRNA expression pattern in CLL lymph node and blood samples was very similar. Three of 15 miRNAs (miR-16, miR-21, and miR-150) showed a high expression level in both blood and lymph node samples. No difference was observed between ZAP-70-positive or -negative and between IgH-mutated or unmutated cases. No correlation was found between miR-15a and miR-16 expression levels and 13q14 deletion in the blood CLL samples. RNA in situ hybridization (ISH) revealed strong homogeneous staining of miR-150 in the tumour cells outside the PCs. In reverse BIC/pri-miR-155 expression was observed mainly in individual cells including prolymphocytes of the PCs. This reciprocal pattern likely reflects the different functions and targets of miR-150 and miR-155.

MicroRNAs in acute leukemia: from biological players to clinical contributors

“…23,25,[50][51][52][53] MiR-155 acts as an oncogene as its introduction in mouse bone marrow resulted in myeloproliferative disorders 54 and B-lineage ALL/lymphoma. 55 The oncogenic effect was mediated by downregulation of SHIP (Src homology 2 domain-containing inositol-5-phosphatase) and C/EBPb.…”

miRNA profiling of B-cell subsets: specific miRNA profile for germinal center B cells with variation between centroblasts and centrocytes

“…In view of the dynamic expression patterns of miR-150 throughout the GC reaction and its absence in proliferation centers of CLL cases, 20 we investigated the possible role of miR-150 in regulation of B-cell homeostasis. One proven target for miR-150, c-Myb, 14 and two putative miR-150 targets, Foxp1 (both PICTAR and TargetScan 4.2 predictions) and Survivin (not predicted by both PICTAR and TargetScan 4.2 programs, but contained miR-150 6mer seed complimentary site at its 3 0 UTR), were examined by immunohistochemistry staining.…”

“…20 CLL cells are considered to be of memory B-cell origin or derived from naïve B cells. 43,44 The high miR-150 expression in CLL is consistent with the high miR-150 expression levels that we found in naïve and memory B cells sorted from normal tonsil, and the lack in proliferation centers is consistent with the low levels in GC structures of tonsil.…”

“…MicroRNAs (miRNAs) are a class of small RNAs of [19][20][21][22][23] nucleotides that were discovered less than two decades ago. 1,2 When incorporated into Argonaute proteins to form the RNAinduced silencing complex, miRNAs can negatively regulate genes at the post-transcriptional level by either triggering translational repression or direct cleavage of mRNAs.…”

“…For example, miR-21, miR-92, miR-150, miR-155 and miR-222 are reported to be deregulated in chronic lymphocytic leukemia (CLL). 19,20 Overexpression of miR-155 as well as the miR-17-92 cluster has been documented for several B-cell lymphomas, including diffuse large B-cell lymphoma and Hodgkin lymphoma. [21][22][23] In a transgenic mouse model, ectopic expression of miR-155 leads to lymphoblastic leukemia/high-grade lymphoma.…”