13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking.
Cell Line
Chromatin Assembly and Disassembly
/ genetics
Chromosome Deletion
Chromosome Disorders
/ complications
Chromosomes, Human, Pair 13
/ genetics
Cohort Studies
DNA Copy Number Variations
/ genetics
Enhancer Elements, Genetic
/ genetics
Gene Expression Regulation, Leukemic
Humans
Microarray Analysis
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
RNA-Seq
Up-Regulation
/ genetics
Whole Genome Sequencing
fms-Like Tyrosine Kinase 3
/ genetics
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
20 08 2020
20 08 2020
Historique:
received:
23
12
2019
accepted:
20
04
2020
pubmed:
10
5
2020
medline:
18
3
2021
entrez:
9
5
2020
Statut:
ppublish
Résumé
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 phosphatidylinositol 3-kinase/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 (BCP) acute lymphoblastic leukemia (ALL) using 5 different patient cohorts (in total including 1418 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.
Identifiants
pubmed: 32384149
pii: S0006-4971(20)61778-5
doi: 10.1182/blood.2019004684
pmc: PMC7498303
doi:
Substances chimiques
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
946-956Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2020 by The American Society of Hematology.
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