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

Chong Chen; Yu Liu; Amy R Rappaport; Thomas Kitzing; Nikolaus Schultz; Zhen Zhao; Aditya S Shroff; Ross A Dickins; Christopher R Vakoc; James E Bradner; Wendy Stock; Michelle M LeBeau; Kevin M Shannon; Scott Kogan; Johannes Zuber; Scott W Lowe

doi:10.1016/j.ccr.2014.03.016

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

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

Authors

Affiliations

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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azepines / pharmacology
Cell Differentiation / genetics
Cell Transformation, Neoplastic / genetics*
Chromosome Deletion
Chromosomes, Human, Pair 7 / genetics
Clustered Regularly Interspaced Short Palindromic Repeats
Drug Resistance, Neoplasm / genetics
Gene Dosage
Haploinsufficiency / genetics
Histone-Lysine N-Methyltransferase / antagonists & inhibitors
Histone-Lysine N-Methyltransferase / genetics*
Humans
Leukemia, Myeloid, Acute / genetics*
Mice
Mice, Inbred C57BL
Myeloid-Lymphoid Leukemia Protein / genetics
RNA Interference
RNA, Small Interfering
Triazoles / pharmacology
Tumor Suppressor Proteins / genetics*

Substances

(+)-JQ1 compound
Azepines
RNA, Small Interfering
Triazoles
Tumor Suppressor Proteins
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
MLL3 protein, mouse

Associated data

GEO/GSE54313

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding