Regulation of myeloid leukaemia by the cell-fate determinant Musashi.

Nature
Takahiro ItoTannishtha Reya

Abstract

Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that ta...Continue Reading

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Citations

Jul 30, 2011·International Journal of Hematology·Florian H HeidelScott A Armstrong
Jun 13, 2012·International Journal of Hematology·Liang HuangJianfeng Zhou
Apr 4, 2013·International Journal of Hematology·Takahiro Ito
Sep 5, 2013·Pathology, Research and Practice·Modjtaba Emadi-BaygiShaghayegh Haghjooy-Javanmard
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Oct 24, 2013·World Journal of Gastroenterology : WJG·Rong-Guang KuangJian-Wen Wang
Jan 18, 2013·Proceedings of the National Academy of Sciences of the United States of America·Manabu KurokawaSally Kornbluth
Feb 4, 2014·Nature Genetics·Bryan ZimdahlTannishtha Reya
Jan 8, 2014·The Journal of Experimental Medicine·Sun-Mi ParkMichael G Kharas
Jun 19, 2013·Cellular and Molecular Life Sciences : CMLS·Sandra Gómez-LópezClaudia Petritsch
Aug 12, 2014·The Journal of Clinical Investigation·Yaoyu ChenShaoguang Li
Jun 28, 2012·Leukemia & Lymphoma·Christian OberenderPhilipp le Coutre
Nov 5, 2014·Leukemia & Lymphoma·Jaspal KaedaPhilipp le Coutre
Feb 9, 2011·Leukemia & Lymphoma·Nicholas J Donato, Luke F Peterson
Sep 5, 2012·The Journal of Cell Biology·Tannishtha Reya
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Jul 15, 2015·International Journal of Molecular Medicine·Chengzhi XieXundi Xu
Dec 17, 2014·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Toshio KitamuraJiro Kitaura
Feb 24, 2015·The Journal of Investigative Dermatology·Mizuho Fukunaga-KalabisMeenhard Herlyn

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Datasets Mentioned

BETA
BC033459

Methods Mentioned

BETA
immunoprecipitation
flow cytometry
PCR
genetrap
FACS
PCRs

Software Mentioned

Enodar
R
ConCise Scanner
GraphPad
[UNK]
GraphPad Prism
FlowJo
Metamorph
Rosetta

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