Browse by author
Lookup NU author(s): Professor Olaf Heidenreich
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.
Author(s): Goyama S, Schibler J, Gasilina A, Shrestha M, Lin S, Link KA, Chen J, Whitman SP, Bloomfield CD, Nicolet D, Assi SA, Ptasinska A, Heidenreich O, Bonifer C, Kitamura T, Nassar NN, Mulloy JC
Publication type: Article
Publication status: Published
Print publication date: 01/03/2016
Online publication date: 09/10/2015
Acceptance date: 30/09/2015
ISSN (print): 0887-6924
ISSN (electronic): 1476-5551
Publisher: Nature Publishing Group
Altmetrics provided by Altmetric