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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Proliferation
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Chromosomes, Human, Pair 21
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Chromosomes, Human, Pair 8
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Core Binding Factor Alpha 2 Subunit / genetics*
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Core Binding Factor Alpha 2 Subunit / metabolism
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fetal Blood / cytology
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Fetal Blood / drug effects
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Fetal Blood / metabolism
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Gene Expression Regulation, Leukemic*
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Heterografts
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, SCID
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Myeloid Cells / cytology
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Myeloid Cells / drug effects
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Myeloid Cells / metabolism
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Preleukemia / genetics*
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Preleukemia / metabolism
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Preleukemia / pathology
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Protein Tyrosine Phosphatases / genetics*
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Protein Tyrosine Phosphatases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-cbl / antagonists & inhibitors
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Proto-Oncogene Proteins c-cbl / genetics*
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Proto-Oncogene Proteins c-cbl / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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RUNX1 Translocation Partner 1 Protein
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Thrombopoietin / pharmacology
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Transgenes
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Translocation, Genetic
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src-Family Kinases / genetics
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src-Family Kinases / metabolism
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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MIRN92 microRNA, human
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MicroRNAs
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Oncogene Proteins, Fusion
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RNA, Small Interfering
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RUNX1 Translocation Partner 1 Protein
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STAT5 Transcription Factor
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Thrombopoietin
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Proto-Oncogene Proteins c-cbl
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src-Family Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Protein Tyrosine Phosphatases
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UBASH3B protein, human
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CBL protein, human