UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

Leukemia. 2016 Mar;30(3):728-39. doi: 10.1038/leu.2015.275. Epub 2015 Oct 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • MIRN92 microRNA, human
  • MicroRNAs
  • Oncogene Proteins, Fusion
  • RNA, Small Interfering
  • RUNX1 Translocation Partner 1 Protein
  • STAT5 Transcription Factor
  • Thrombopoietin
  • Proto-Oncogene Proteins c-cbl
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Tyrosine Phosphatases
  • UBASH3B protein, human
  • CBL protein, human