STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia

Abstract

We recently identified the CDC25A phosphatase as a key actor in proliferation and differentiation in acute myeloid leukemia which expresses the FLT3-ITD mutation. In this paper we demonstrate that CDC25A level is controlled by a complex STAT5/miR-16 transcription and translation pathway working downstream of this receptor. First, we established by CHIP analysis that STAT5 is directly involved in FLT3-ITD-dependent CDC25A gene transcription. In addition, we determined that miR-16 expression is repressed by FLT3-ITD activity, and that STAT5 participates in this repression. In accordance with these results, miR-16 expression was significantly reduced in a panel of AML primary samples carrying the FLT3-ITD mutation when compared with FLT3wt cells. The expression of a miR-16 mimic reduced CDC25A protein and mRNA levels, and RNA interference-mediated down modulation of miR-16 restored CDC25A expression in response to FLT3-ITD inhibition. Finally, decreasing miR-16 expression partially restored the proliferation of cells treated with the FLT3 inhibitor AC220, while the expression of miR-16 mimic stopped this proliferation and induced monocytic differentiation of AML cells. In summary, we identified a FLT3-ITD/STAT5/miR-16/CDC25A axis essential for AML cell proliferation and differentiation.

The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression

“…6D). Among the 3’UTRs that showed GFP repression upon miR-15a/16-1 overexpression were some prominent cell cycle regulating genes such as Ccne1, Wee1, Cdc25 and Chek1 , some of which have already been described as miR-15 family-regulated targets (Lindner et al 2017; Mei et al 2015; Sueur et al 2020). To validate these findings, the upregulation of a selected set of genes in response to miR-15 knockout was confirmed by qPCR analysis (Fig.…”

“…With respect to its tumor suppressive role, the miR-15 family has been connected to several hematologic malignancies including CLL, in which more than 60% of patients display a genomic deletion comprising the miR-15a/16-1 cluster. Accordingly, loss of either miR-15a/16-1 or miR-CDC25A, which has been reported to be regulated by miR-16 in an AML subtype (FLT3-ITD AML) and serves as a critical factor for AML development (Sueur et al 2020). In accordance with the already described role of miR-16 in Cdc25a repression, our data confirm Cdc25a as direct miR-15 target gene in the B cell setting.…”

“…CDC25A, which has been reported to be regulated by miR-16 in an AML subtype (FLT3-ITD AML) and serves as a critical factor for AML development (Sueur et al 2020). In accordance with the already described role of miR-16 in Cdc25a repression, our data confirm Cdc25a as direct miR-15 target gene in the B cell setting.…”