Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression

Abstract

B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, occurs in two forms, aggressive (showing for the most part high ZAP-70 expression and unmutated IgH V H ) and indolent (showing low ZAP-70 expression and mutated IgH V H ). We found that miR-29a is up-regulated in indolent human B-CLL as compared with aggressive B-CLL and normal CD19 + B cells. To study the role of miR-29 in B-CLL, we generated Eμ-miR-29 transgenic mice overexpressing miR-29 in mouse B cells. Flow cytometric analysis revealed a markedly expanded CD5 + population in the spleen of these mice starting at 2 mo of age, with 85% (34/40) of miR-29 transgenic mice exhibiting expanded CD5 + B-cell populations, a characteristic of B-CLL. On average, 50% of B cells in these transgenic mice were CD5 positive. At 2 y of age the mice showed significantly enlarged spleens and an increase in the CD5 + B-cell population to ∼100%. Of 20 Eμ-miR-29 transgenic mice followed to 24-26 mo of age, 4 (20%) developed frank leukemia and died of the disease. These results suggest that dysregulation of miR-29 can contribute to the pathogenesis of indolent B-CLL.mouse models | microRNA C hronic lymphocytic leukemia (CLL) is the most common human leukemia, accounting for ∼30% of all cases (1), with ∼10,000 new cases observed each year in the United States. Characteristically, CLL is a disease of elderly people, with the incidence increasing linearly with each decade above age 40 y (1, 2). It is known that this disease is characterized by the clonal expansion of CD5 + B cells (2).MicroRNAs, representing between 1% and 3% of all eukaryotic genes, are a class of endogenous noncoding RNAs, 19-25 nt in size, which regulate gene expression at the transcriptional or translational level (3). Approximately half of human microRNAs are located at fragile sites and genomic regions involved in alterations in cancers (4), and alteration of microRNA expression profiles occurs in most cancers, suggesting that individual microRNAs could function as tumor suppressors or oncogenes (5).The 13q14 deletion is the most common CLL aberration and is detected by cytogenetic analysis in approximately half of the cases (6). Analysis of a deletion at 13q14.3 led to the discovery of two physically linked microRNAs, miR-15a and miR-16-1, as targets of these deletions (7). Consequently, miR-15a and miR-16-1 expression is reduced in the majority of CLL cases (7), and further studies indicated that miR-15a/miR-16-1 negatively regulate Bcl2 expression (8). These findings indicated that microRNAs play important roles in CLL and that down-regulation of miR-15/16 and subsequent Bcl2 up-regulation contribute to CLL pathogenesis (7). Because miR-15/16 was identified as a tumor suppressor in indolent CLL, the microRNA expression profile in CLL has been studied extensively, and a signature profile was reported describing 13 microRNAs that differentiate aggressive and indolent CLL (4).We and others observed that miRNA-29 expression is downregulated in aggressive CLL as compared ...

microRNA-29b: an Emerging Player in Human Cancer

“…In aggressive B-CLL, however, miR-29b may directly target several important oncogenes. Consistent with the findings in other types of cancer, miR-29b probably shows a tumor suppressive function in B cell (Santanam et al, 2010;Kincaid et al, 2012;Liston et al, 2012). Thus, miR-29b can protect normal cells by regulating tumor immunosurveillance.…”

Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL)

“…5). We recently reported significantly higher miR-29a and miR-29b expression levels in indolent CLL compared with normal CD19 + B cells (17). To study the role of miR-29 in CLL, we generated Eμ-miR-29 transgenic mice overexpressing miR-29 in B cells, and found that these mice developed a disease similar to indolent CLL (17).…”

“…We recently reported significantly higher miR-29a and miR-29b expression levels in indolent CLL compared with normal CD19 + B cells (17). To study the role of miR-29 in CLL, we generated Eμ-miR-29 transgenic mice overexpressing miR-29 in B cells, and found that these mice developed a disease similar to indolent CLL (17). Given that DNMT3A is a known miR-29 target (16), we analyzed its expression in Eμ-miR-29 transgenics, and found down-regulated Dnmt3A expression in Eμ-miR-29 transgenic mice (17).…”

MicroRNA expression by an oncogenic retrovirus

“…Importantly, an MDV mutant lacking the viral miR-155 analog grows normally in culture, yet is no longer capable of causing lymphomas in experimentally infected chickens (15). Similarly, miR-29 overexpression is causatively linked to CLL in humans and mice (4), and BLV causes B-cell tumors that closely resemble CLL (5). By analogy to MDV and miR-155, it would certainly be very interesting to see if a BLV mutant lacking miR-B4 loses the ability to induce B-cell tumors in infected ruminants.…”

“…Moreover, one of the BLV miRNAs, miR-B4, shares the same seed sequence as cellular miR-29 and therefore can down-regulate many of the same mRNA targets. As miR-29 overexpression can induce chronic lymphocytic leukemia (CLL) in transgenic mice (4), and BLV induces CLL-like B-cell neoplasms in infected cattle and sheep (5), it appears likely that these viral miRNAs play an important role in BLV pathogenesis.…”