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Cancer Cell. 2014 May 12;25(5):652-65. doi: 10.1016/j.ccr.2014.03.016. Epub 2014 May 1.

MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia.

Author information

1
Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
3
Computational Biology Center, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02215, USA.
6
Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
7
Department of Pediatrics, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
8
Department of Laboratory Medicine & Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
9
Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA; Research Institute of Molecular Pathology, 1030 Vienna, Austria.
10
Cancer Biology and Genetics Program, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.

Abstract

Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease.

PMID:
24794707
PMCID:
PMC4206212
DOI:
10.1016/j.ccr.2014.03.016
[Indexed for MEDLINE]
Free PMC Article

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