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Title: Mutation Order Affects Tumor Evolution and Clinical Course of Disease      
dateReleased:
11-17-2014
description:
Background: Cancers result from accumulation of somatic mutations and their properties are thought to reflect the sum of these mutations. However, little is known about the consequences of altering the order of mutation acquisition. Methods: Mutation order was determined in myeloproliferative neoplasm patients by genotyping hematopoietic colonies or next generation sequencing. Stem and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. Results: Age of presentation, acquisition of JAK2V617F homozygosity and the balance of immature progenitors were all influenced by mutation order. Compared to TET2-first patients, JAK2-first patients had an increased likelihood of presenting with polycythemia vera than essential thrombocythemia, an increased risk of thrombosis and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. In studies of single hematopoietic stem and progenitor cells (HSPCs), mutation order influenced the proliferative response to JAK2V617F and the capacity of double-mutant HSPCs to generate colony-forming cells. Moreover the HSPC compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2/TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2V617F in a cell-intrinsic manner, and prevented JAK2V617F from up-regulating genes associated with proliferation. These data demonstrate that mutation order influences progenitor proliferation and terminal cell expansion, thus influencing clinical presentation, thrombosis risk and progenitor response to targeted therapy. Conclusions: The order in which JAK2 and TET2 mutations are acquired influences clinical features, stem/progenitor cell biology and clonal evolution in patients with myeloproliferative neoplasms.
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-MTAB-3086
refinement:
raw
dateSubmitted:
10-27-2011
keywords:
functional genomics
dateModified:
12-08-2014
availability:
available
types:
gene expression
name:
Homo sapiens
name:
genotype design
ID:
A-MEXP-1171
name:
Illumina HumanHT-12 v3.0 Expression BeadChip
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-MTAB-3086/E-MTAB-3086.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-MTAB-3086/E-MTAB-3086.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress

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