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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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Guo S,Bai H,Megyola CM,Halene S,Krause DS,Scadden DT,Lu J

doi

10.1073/pnas.1213196109

subject

Has Abstract

pub_date

2012-10-09 00:00:00

pages

16636-41

issue

41

eissn

0027-8424

issn

1091-6490

pii

1213196109

journal_volume

109

pub_type

杂志文章

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