Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation
Abstract
Additional sex combs like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. Chromatin immunoprecipitation followed by next-generation sequencing analysis demonstrated opposing effects of wild-type and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 11, 2018
- Source ID
- 10.1084/jem.20171151
Entities
People
- Akinori Kanai
- Alessandro Pastore
- Daichi Inoue
- Hiroaki Honda
- Hsin-an Hou
- Hwei-fang Tien
- Kimihito Cojin Kawabata
- Makoto Saika
- Norimasa Yamasaki
- Omar Abdel-Wahab
- Reina Nagase
- Reina Takeda
- Sayuri Horikawa
- Shuhei Asada
- Susumu Goyama
- Takeshi Fujino
- Toshio Kitamura
- Yasunori Ota
- Yasutaka Hayashi
- Yasuyuki Sera
Organizations
- Edward P. Evans Foundation
- Hiroshima University
- Japan Society for the Promotion of Science
- Leukemia & Lymphoma Society
- Memorial Sloan Kettering Cancer Center
- The Starr Foundation
- Tokyo Women's Medical University
- Uehara Memorial Foundation
- United States Department of Defense
- University of Tokyo