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Series GSE110378 Query DataSets for GSE110378
Status Public on Jul 17, 2019
Title Kdm6b is Required for Self-Renewal of Normal and Leukemic Stem Cells Under Proliferative Stress
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Recent studies have indicated that the histone 3 lysine 27 (H3K27me2/3) demethylase KDM6B (JMJD3) is frequently upregulated in a myriad of blood disorders including myelodysplastic syndrome (MDS), T-cell acute lymphoblastic leukemia (T-ALL), and multiple myeloma (MM) suggesting it may have important functions in the pathogenesis of hematopoietic cancers. Here, we sought to determine the role of Kdm6b in hematopoietic stem cell (HSC) fate decisions under normal and malignant conditions to evaluate its potential as a therapeutic target. We show that loss of Kdm6b leads to a significant reduction in phenotypic and functional HSCs in adult mice, and that Kdm6b is necessary for HSC self-renewal in response to inflammatory, genotoxic and oncogenic stress. Additionally, we show that loss of Kdm6b in HSCs leads to a stress-response gene expression signature in native HSCs that is independent of its demethylase activity. Loss of Kdm6b lead to increased expression of a subset of genes implicated in HSC quiescence (e.g. Fos, Jun, Ier2, Dusp1, Zfp36). Upon inflammatory or replicative stress, HSCs deficient for Kdm6b are not able to efficiently resolve this gene expression program, leading to increased quiescence and a self-renewal block, forcing them to differentiate. These findings show that Kdm6b is necessary for self-renewal of normal and leukemic stem cells, and suggest inhibiting Kdm6b in blood cancers in the presence of proliferative agents may force differentiation and eventual depletion of leukemic stem cells.
 
Overall design Hematopoietic stem cells (HSCs) were sorted from Vav-CRE:Control and Vav-CRE:Kdm6b-KO mice for RNA-seq to determine gene expression and ChIPmentation for H3K27me3 and H3K4me3 chromatin markers
 
Contributor(s) Mallaney C, Ostrander EL, Celik H, Kramer AC, Martens A, Kothari A, Koh WK, Haussler E, Challen GA
Citation(s) 30936419
Submission date Feb 08, 2018
Last update date Oct 08, 2019
Contact name Grant A Challen
E-mail(s) grantchallen@wustl.edu
Phone 3143620987
Organization name Washington University School of Medicine
Department Medicine
Street address 660 Euclid Avenue
City St Louis
State/province MO
ZIP/Postal code 63110
Country USA
 
Platforms (1)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (20)
GSM2989276 Control RNA-seq 1
GSM2989277 Control RNA-seq 2
GSM2989278 Control RNA-seq 3
Relations
BioProject PRJNA433558
SRA SRP132516

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE110378_RAW.tar 2.5 Gb (http)(custom) TAR (of BW, NARROWPEAK, TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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