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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

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

Author

  • 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

Summary, in English

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.

Department/s

  • LUCC: Lund University Cancer Centre
  • Aneuploidy in cancer
  • Division of Clinical Genetics
  • Molecular Lymphopoiesis
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • Translational Genomic and Functional Studies of Leukemia
  • Genetic chaos in aggressive cancer

Publishing year

2020-08-20

Language

English

Pages

946-956

Publication/Series

Blood

Volume

136

Issue

8

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Medical Genetics
  • Hematology

Status

Published

Research group

  • Aneuploidy in cancer
  • Molecular Lymphopoiesis
  • Translational Genomic and Functional Studies of Leukemia
  • Genetic chaos in aggressive cancer

ISBN/ISSN/Other

  • ISSN: 0006-4971