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Cancer Cell. 2016 Nov 14;30(5):737-749. doi: 10.1016/j.ccell.2016.10.008.

Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia.

Author information

1
Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
2
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
3
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
4
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Oxford OX3 9DS, UK.
5
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
6
Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: james.mulloy@cchmc.org.
7
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. Electronic address: mthirman@medicine.bsd.uchicago.edu.

Abstract

The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34+ cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. Such incongruity was also observed in t(4;11) patients in whom leukemia evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.

KEYWORDS:

MLL-AF4; acquired resistance to targeted therapy; acute lymphoblastic leukemia; chimeric fusion proteins; mouse models of cancer; species specificity of oncogenes

PMID:
27846391
DOI:
10.1016/j.ccell.2016.10.008
[Indexed for MEDLINE]
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