ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

Jean-Baptiste Micol,Benjamin H Durham,Amit Sinha,Eric Solary,Young Rock Chung,Omar Abdel-Wahab,Eunhee Kim,Akihide Yoshimi,Nicolas Duployez,Hana Cho,Claude Preudhomme,Daichi Inoue,Alessandro Pastore,Andrei Krivtsov,Stanley Chun-Wei Lee,Xiao Jing Zhang,Richard Koche

doi:10.1038/ncomms15429

Abstract

Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.

Highlights

Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila
Given the likely different enrichment efficiencies between antibodies used in ChIP-seq here and the different number of peaks across the different immunoprecipitated proteins, we evaluated the percentage of ASXL2, AML1-ETO and RUNX1 peaks that overlap with promoters
Mutations in the polycomb-associated protein ASXL1 are present across the myeloid neoplasms and ubiquitously associated with adverse clinical outcome in every subtype of myeloid leukemia[7,8,49,50,51]

Summary

Introduction

Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl[2] is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO. We set out to define the role of ASXL2 in normal and malignant haematopoiesis, to compare its effects on gene expression and chromatin state to those of ASXL1, and to understand the functional basis for ASXL2 mutations in the context of AML1-ETO-mediated AML. Loss of Asxl[2] altered chromatin state at key leukemogenic loci in AML1-ETO-expressing cells and loss of even a single copy of Asxl[2] promotes AML1-ETO leukemogenesis

Methods

Results

Conclusion