Complex oncogene dependence in microRNA-125a–induced myeloproliferative neoplasms

Abstract

Deregulation of microRNA (miRNA) expression can lead to cancer initiation and progression. However, limited information exists on the function of miRNAs in cancer maintenance. We examined these issues in the case of myeloproliferative diseases and neoplasms (MPN), a collection of hematopoietic neoplasms regarded as preleukemic, thereby representing early neoplastic states. We report here that microRNA-125a (miR-125a)–induced MPN display a complex manner of oncogene dependence. Following a gain-of-function genomics screen, we overexpressed candidate miR-125a in vivo, which led to phenotypes consistent with an atypical MPN characterized by leukocytosis, monocytosis, splenomegaly, and progressive anemia. The diseased MPN state could be recapitulated in a doxycycline-inducible mouse model. Upon doxycycline withdrawal, the primary MPN phenotypes rapidly resolved after the discontinuation of miR-125a overexpression. However, reinduction of miR-125a led to complex phenotypes, with some animals rapidly developing lethal anemia with extensive damages in the spleen. Forced expression of miR-125a resulted in elevated cellular tyrosine phosphorylation and hypersensitivity toward hematopoietic cytokines. Furthermore, we demonstrate that miR-125a targets multiple protein phosphatases. Our data demonstrate that miR-125a–induced MPN is addicted to its sustained overexpression, and highlight the complex nature of oncogenic miRNA dependence in an early neoplastic state.

MAP3K11 is a tumor suppressor targeted by the oncomiR miR-125b in early B cells

“…These observations are in line with data showing an anti-apoptotic effect of miR-125b, especially in the absence of growth factors or low-serum conditions, in several in vitro systems. 24,26,37,38 However, in contrast to others, we find only a limited impact of miR-125b on pre-B-cell proliferation, suggesting that this oncomiR has the dual potential to affect proliferative as well as apoptotic signaling pathways, depending on the priming events or cellular context. 26 The noted discrepancy, however, may be reconciled by the fact that in contrast to primary wild-type B-cell precursors, 1676 cells proliferate already at a high rate that can simply not be enhanced further by miR-125b.…”

Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias

“…In support of this notion, it was recently shown that survival of myeloid leukemic cells induced by miR-125a requires continual overexpression of this microRNA and removal of miR125a after cancer development was accompanied by regression of the leukemia. 30 Furthermore, we established that miR-125b functions within both HSPCs and MPs to drive a myeloproliferative disorder in vitro. Indeed, transplanting miR-125b-overexpressing MPs could induce leukemia in recipient mice.…”

Identification of miR-125a-5p as a tumor suppressor of renal cell carcinoma, regulating cellular proliferation, migration and apoptosis

“…miRNAs are short, single-stranded RNAs which are associated with gene regulation, at both the transcriptional and translational level, by base-pairing to complementary mRNA sequences in their target genes (17). MiRNAs have diverse functions and are involved in a variety of biochemical processes, including cellular differentiation, proliferation, apoptosis, metabolism and disease, including cancer (18).…”