Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15429
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Funding
- Fondation de France
- Philippe Foundation
- Japan Society for the Promotion of Science
- YASUDA Medical Foundation
- Kanae Foundation for the Promotion of Medical Science
- Worldwide Cancer Research Fund
- Leukemia and Lymphoma Society (LLS) Special Fellow Award
- American Society of Hematology (ASH)
- Aplastic Anemia and MDS Research Foundation
- Edward P. Evans Foundation
- Dept. of Defense Bone Marrow Failure Research Program [BM150092, W81XWH-12-1-0041]
- NIH/NHLBI [R01 HL128239]
- NIH K08 Clinical Investigator Award [1K08CA160647-01]
- Josie Robertson Investigator Program
- Damon Runyon Clinical Investigator Award
- Starr Foundation [I8-A8-075]
- Leukemia and Lymphoma Society
- Pershing Square Sohn Cancer Research Alliance
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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.
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