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

Minjun Yang, Setareh Safavi, Eleanor L Woodward, Nicolas Duployez, Linda Olsson-arvidsson, Jonas Ungerbäck, Mikael Sigvardsson, Marketa Zaliova, Jan Zuna, Thoas Fioretos, Bertil Johansson, Karolin H Nord, Kajsa Paulsson

Research output: Contribution to journalArticlepeer-review

7 Citations (SciVal)

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.
Original languageEnglish
Pages (from-to)946-956
Number of pages11
JournalBlood
Volume136
Issue number8
Early online date2020 May 8
DOIs
Publication statusPublished - 2020 Aug 20

Subject classification (UKÄ)

  • Medical Genetics
  • Hematology

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