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

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.

Highlights

Acute myeloid leukemia (AML) comprises a series of clinically and genetically heterogeneous cancers that are caused by mutations that drive aberrant proliferation and impaired differentiation of hematopoietic stem and progenitor cells (HSPC)
Analysis of 7q Alterations in Human Myeloid Neoplasms As a step toward understanding and modeling the genetic and molecular changes that contribute to the aggressive nature of complex karyotype (CK) AML, we analyzed the genome profiles of adult AML harboring normal and complex karyotypes
By analyzing array-based comparative genomic hybridization data sets produced in our laboratory, we identified one relapse normal karyotype (NK) AML case harboring a focal deletion (8.8 Mb) at 7q35-36 encompassing the mixed lineage leukemia 3 (MLL3) gene (Figure S1A available online)

Summary

Introduction

Acute myeloid leukemia (AML) comprises a series of clinically and genetically heterogeneous cancers that are caused by mutations that drive aberrant proliferation and impaired differentiation of hematopoietic stem and progenitor cells (HSPC). Some subsets of AML harbor large chromosomal deletions the impact of which on leukemia biology and treatment is poorly understood. Monosomy 7 or large deletions of 7q (À7/del(7q)) are associated with myelodysplastic syndrome (MDS) and AML, and often occur together with À5/del(5q) and del(17p) in the context of complex karyotype (CK) AML (Mrozek, 2008). Such mutations are common in myeloid neoplasms arising in patients treated with alkylating agents for a previous cancer (Qian et al, 2010). Unlike AMLs with other abnormalities, these malignancies are largely refractory to conventional chemotherapy and represent an AML subset for which new treatments are urgently needed (Dohner et al, 2010; Grimwade et al, 2010)

Results

Discussion

Conclusion