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

Jean-Baptiste Micol, Alessandro Pastore, Daichi Inoue, Nicolas Duployez, Eunhee Kim, Stanley Chun-Wei Lee, Benjamin H. Durham, Young Rock Chung, Hana Cho, Xiao Jing Zhang, Akihide Yoshimi, Andrei Krivtsov, Richard Koche, Eric Solary, Amit Sinha, Claude Preudhomme and Omar Abdel-Wahab ()
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Jean-Baptiste Micol: Inserm UMR1170, Gustave Roussy Cancer Campus Grand Paris
Alessandro Pastore: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Daichi Inoue: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Nicolas Duployez: Laboratory of Hematology and Tumor Bank, INSERM UMR-S 1172, Cancer Research Institute of Lille, CHRU of Lille, University Lille Nord de France
Eunhee Kim: School of Life Sciences, Ulsan National Institute of Science and Technology
Stanley Chun-Wei Lee: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Benjamin H. Durham: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Young Rock Chung: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Hana Cho: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Xiao Jing Zhang: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Akihide Yoshimi: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College
Andrei Krivtsov: Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School
Richard Koche: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Eric Solary: Inserm UMR1170, Gustave Roussy Cancer Campus Grand Paris
Amit Sinha: Basepair, Inc.
Claude Preudhomme: Laboratory of Hematology and Tumor Bank, INSERM UMR-S 1172, Cancer Research Institute of Lille, CHRU of Lille, University Lille Nord de France
Omar Abdel-Wahab: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15429

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