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

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  • Jean-Baptiste Micol

    (Inserm UMR1170, Gustave Roussy Cancer Campus Grand Paris
    Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre
    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College)

  • 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
    Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre)

  • 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
    Leukemia Service, Dept. of Medicine, Memorial Sloan Kettering Cancer Center)

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.

Suggested Citation

  • 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 & , 2017. "ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15429
    DOI: 10.1038/ncomms15429
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    Cited by:

    1. Nidhi Rohatgi & Wei Zou & Yongjia Li & Kevin Cho & Patrick L. Collins & Eric Tycksen & Gaurav Pandey & Carl J. DeSelm & Gary J. Patti & Anwesha Dey & Steven L. Teitelbaum, 2023. "BAP1 promotes osteoclast function by metabolic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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