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)
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 Cancer Center Program > Gene Regulation and Cell Proliferation CSHL labs > Vakoc lab School of Biological Sciences > Publications |
| Depositing User: | Matt Covey |
| Date: | 30 April 2014 |
| Date Deposited: | 09 Jun 2014 16:26 |
| Last Modified: | 16 Jul 2021 16:22 |
| PMCID: | PMC4206212 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30282 |
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