title: UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO.
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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Goyama
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Schibler
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gasilina
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shrestha
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lin
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Link
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Whitman
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nicolet
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Assi
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: A
authors.initials: A
authors.lastname: Ptasinska
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: O
authors.identifier: http://orcid.org/0000-0001-5404-6483
authors.initials: O
authors.lastname: Heidenreich
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: C
authors.initials: C
authors.lastname: Bonifer
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: N N
authors.initials: NN
authors.lastname: Nassar
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Mulloy
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011289:Preleukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013926:Thrombopoietin / Q000494:pharmacology; D019076:Transgenes; D014178:Translocation, Genetic; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D050799:STAT5 Transcription Factor; D013926:Thrombopoietin; D050721:Proto-Oncogene Proteins c-cbl; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D017027:Protein Tyrosine Phosphatases; C489397:UBASH3B protein, human; C067419:CBL protein, human