RRC ID 53216
Author 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.
Title UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO.
Journal Leukemia
Abstract 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.
Volume 30(3)
Pages 728-39
Published 2016-3-1
DOI 10.1038/leu.2015.275
PII leu2015275
PMID 26449661
PMC PMC4775400
MeSH Animals Cell Proliferation Chromosomes, Human, Pair 21 Chromosomes, Human, Pair 8 Core Binding Factor Alpha 2 Subunit / genetics* Core Binding Factor Alpha 2 Subunit / metabolism Extracellular Signal-Regulated MAP Kinases / genetics Extracellular Signal-Regulated MAP Kinases / metabolism Fetal Blood / cytology Fetal Blood / drug effects Fetal Blood / metabolism Gene Expression Regulation, Leukemic* Heterografts Humans Leukemia, Myeloid, Acute / genetics* Leukemia, Myeloid, Acute / metabolism Leukemia, Myeloid, Acute / pathology Mice Mice, SCID MicroRNAs / genetics MicroRNAs / metabolism Myeloid Cells / cytology Myeloid Cells / drug effects Myeloid Cells / metabolism Oncogene Proteins, Fusion / genetics* Oncogene Proteins, Fusion / metabolism Preleukemia / genetics* Preleukemia / metabolism Preleukemia / pathology Protein Tyrosine Phosphatases / genetics* Protein Tyrosine Phosphatases / metabolism Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-cbl / antagonists & inhibitors Proto-Oncogene Proteins c-cbl / genetics* Proto-Oncogene Proteins c-cbl / metabolism RNA, Small Interfering / genetics RNA, Small Interfering / metabolism RUNX1 Translocation Partner 1 Protein STAT5 Transcription Factor / genetics STAT5 Transcription Factor / metabolism Thrombopoietin / pharmacology Transgenes Translocation, Genetic src-Family Kinases / genetics src-Family Kinases / metabolism
IF 8.665
Times Cited 24
Cord blood stem cells for research