title: PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease.
abstract: Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting the MEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. chen3jj@uc.edu zli7@bsd.uchicago.edu.
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Rui
authors.initials: R
authors.lastname: Su
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio. Institute of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Hu
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Hengyou
authors.initials: H
authors.lastname: Weng
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio. Institute of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yungui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Shenglai
authors.initials: S
authors.lastname: Li
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
authors.forename: Gang Greg
authors.initials: GG
authors.lastname: Wang
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Liu
authors.affiliation: Institute of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio. chen3jj@uc.edu zli7@bsd.uchicago.edu.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C090466:proto-oncogene protein Pbx3; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase