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13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking

Yang, Minjun LU ; Safavi, Setareh LU ; Woodward, Eleanor L LU ; Duployez, Nicolas ; Olsson-arvidsson, Linda ; Ungerbäck, Jonas LU ; Sigvardsson, Mikael LU ; Zaliova, Marketa ; Zuna, Jan and Fioretos, Thoas LU , et al. (2020) In Blood 136(8). p.946-956
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
136
issue
8
pages
11 pages
publisher
American Society of Hematology
external identifiers
  • pmid:32384149
  • scopus:85088953308
ISSN
0006-4971
DOI
10.1182/blood.2019004684
language
English
LU publication?
yes
id
18d367be-2978-4c27-a25a-fcad58eaa9eb
date added to LUP
2020-05-26 06:49:52
date last changed
2022-04-18 22:22:40
@article{18d367be-2978-4c27-a25a-fcad58eaa9eb,
  abstract     = {{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.}},
  author       = {{Yang, Minjun and Safavi, Setareh and Woodward, Eleanor L and Duployez, Nicolas and Olsson-arvidsson, Linda and Ungerbäck, Jonas and Sigvardsson, Mikael and Zaliova, Marketa and Zuna, Jan and Fioretos, Thoas and Johansson, Bertil and Nord, Karolin H and Paulsson, Kajsa}},
  issn         = {{0006-4971}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  pages        = {{946--956}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking}},
  url          = {{http://dx.doi.org/10.1182/blood.2019004684}},
  doi          = {{10.1182/blood.2019004684}},
  volume       = {{136}},
  year         = {{2020}},
}