13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F20%3A10412729" target="_blank" >RIV/00216208:11130/20:10412729 - isvavai.cz</a>
Alternative codes found
RIV/00064203:_____/20:10412729
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=G5fxBDLM-l" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=G5fxBDLM-l</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1182/blood.2019004684" target="_blank" >10.1182/blood.2019004684</a>
Alternative languages
Result language
angličtina
Original language name
13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking
Original language description
Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the PI3K/AKT, RAS/MAPK and STAT5 signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.2 microdeletions in B-cell precursor acute lymphoblastic leukemia (BCP ALL) using five different patient cohorts, in total including 1,418 cases. The 13q12.2 deletions occur immediately 5' of FLT3 and involve the PAN3 locus. By detailed analysis of the 13q12.2 segment, we show that the deletions lead to loss of a topologically associating domain border and an enhancer of FLT3. This results in increased cis-interactions between the FLT3 promoter and another enhancer located distally to the deletion breakpoints, with subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent activation of the receptor and downstream signaling. The 13q12.2 deletions are highly enriched in the high hyperdiploid BCP ALL subtype (frequency 3.9% vs. 0.5% in other BCP ALL) and in cases that subsequently relapsed. Taken together, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via chromatin remodeling and enhancer hijacking. These data further emphasize the role of FLT3 as a driver gene in BCP ALL.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
<a href="/en/project/NV15-30626A" target="_blank" >NV15-30626A: High-throughput genomic profiling for personalised diagnostics and treatment of haematopoietic disorders in children</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Blood
ISSN
0006-4971
e-ISSN
—
Volume of the periodical
136
Issue of the periodical within the volume
8
Country of publishing house
US - UNITED STATES
Number of pages
11
Pages from-to
946-956
UT code for WoS article
000565193300008
EID of the result in the Scopus database
2-s2.0-85088953308