MLL3 Is a Haploinsufficient 7q Tumor Suppressor in Acute Myeloid Leukemia

Chen, C., Liu, Y., Rappaport, A. R., Kitzing, T., Schultz, N., Zhao, Z., Shroff, A. S., Dickins, R. A., Vakoc, C. R., Bradner, J. E., Stock, W., Lebeau, M. M., Shannon, K. M., Kogan, S., Zuber, J., Lowe, S. W. (April 2014) MLL3 Is a Haploinsufficient 7q Tumor Suppressor in Acute Myeloid Leukemia. Cancer Cell, 25 (5). pp. 652-665. ISSN 1878-3686 (Electronic)1535-6108 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/24794707
DOI: 10.1016/j.ccr.2014.03.016

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 approximately 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomes, structure and function
diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:
Communities: CSHL labs > Vakoc lab
Watson School > Publications
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: Matt Covey
Date: 30 April 2014
Date Deposited: 09 Jun 2014 16:26
Last Modified: 06 Oct 2015 19:32
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30282

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