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Cancer Res. 2016 Feb 1;76(3):619-29. doi: 10.1158/0008-5472.CAN-15-1566. Epub 2016 Jan 8.

PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease.

Author information

1
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. chen3jj@uc.edu zli7@bsd.uchicago.edu.
2
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
3
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
4
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.
5
Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
6
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
7
Department of Pathology, University of Chicago, Chicago, Illinois.
8
UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
9
Institute of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China.
10
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.

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.

PMID:
26747896
PMCID:
PMC4810030
DOI:
10.1158/0008-5472.CAN-15-1566
[Indexed for MEDLINE]
Free PMC Article

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