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Series GSE111067 Query DataSets for GSE111067
Status Public on Feb 28, 2018
Title Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary 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. Here 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 morphologic 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. ChIP-seq analysis demonstrated opposing effects of wildtype 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.
 
Overall design Asxl1 mutant knock-in mouse model mimicking CHIP
 
Contributor(s) Nagase R, Inoue D, Pastore A, Fujino T, Hou H, Yamasaki N, Goyama S, Saika M, Kanai A, Sera Y, Horikawa S, Ota Y, Asada S, Hayashi Y, Kawabata K, Takeda R, Tien H, Honda H, Abdel-Wahab O, Kitamura T
Citation(s) 28516957
Submission date Feb 23, 2018
Last update date Mar 19, 2019
Contact name Omar Abdel-Wahab
E-mail(s) abdelwao@mskcc.org
Organization name MSKCC
Department HOPP
Lab Abdel-Wahab
Street address 1275 York Ave
City New York
State/province NY
ZIP/Postal code 10065
Country USA
 
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (12)
GSM3021549 Asxl1-mu-KI-BM_FLAG
GSM3021550 Control-BM_ASXL1
GSM3021551 Asxl1-mu-KI-BM_ASXL1
Relations
BioProject PRJNA435741
SRA SRP133391

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Supplementary file Size Download File type/resource
GSE111067_RAW.tar 3.5 Gb (http)(custom) TAR (of BW, TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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