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Series GSE112024 Query DataSets for GSE112024
Status Public on Sep 01, 2019
Title Cell-intrinsic Depletion of Aml1-ETO-positive Pre-leukemic HSCs by K-Ras Activating Mutation
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Somatic mutations in acute myeloid leukemia (AML) are acquired sequentially and hierarchically. First, pre-leukemic mutations, such as t(8;21) that encodes AML1-ETO, are acquired within the hematopoietic stem cell (HSC) compartment, while signaling pathway mutations, including K-RAS activating mutations, are late events acquired during transformation of leukemic progenitor cells and rarely detectable in HSCs. This raises the possibility that signaling pathway mutations are detrimental to clonal expansion of pre-leukemic HSCs. To address this hypothesis we here used conditional genetics to introduce Aml1-ETO and K-RasG12D into murine HSCs, either individually or in combination. In the absence of activated Ras, Aml1-ETO expression conferred a competitive advantage to HSCs. However, activated K-Ras had a marked detrimental effect on Aml1-ETO expressing HSCs, leading to loss of both phenotypic and functional HSCs. Cell cycle analysis revealed a loss of quiescence in HSCs co-expressing Aml1-ETO and K-RasG12D, accompanied by an enrichment in E2F and Myc target gene expression and depletion of HSC self-renewal-associated gene expression. These findings provide a mechanistic basis for the observed absence of KRAS, and potentially other, signaling mutations in the pre-malignant HSC compartment.
 
Overall design RNA-sequencing of bulk LSKCD150+Flt3-CD45.2+ cells from five different competitively transplanted recipients of WT, Aml1ETO/+, KrasG12D/+ and Aml1ETO/+;KrasG12D/+ fetal liver cells eight weeks post-poly(I:C)
 
Contributor(s) Di Genua C, Mead A, Nerlov C
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Submission date Mar 19, 2018
Last update date Sep 01, 2019
Contact name Cristina Di Genua
E-mail(s) cristina.digenua@ndcls.ox.ac.uk
Organization name University of Oxford
Department Weatherall Institute of Molecular Medicine
Street address Headley Way
City Oxford
ZIP/Postal code OX3 9DS
Country United Kingdom
 
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (23)
GSM3053074 1B2_S16
GSM3053075 48B1_S23
GSM3053076 49B1_S7
Relations
BioProject PRJNA438971
SRA SRP136012

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
GSE112024_rpkm_table.txt.gz 2.2 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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