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.

Childhood Leukaemia Investigation Prague Prague Czech Republic

Department of Clinical and Experimental Medicine Linköping University Linköping Sweden

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University University Hospital Motol Prague Czech Republic; and

Division of Clinical Genetics Department of Laboratory Medicine Lund University Lund Sweden

Division of Laboratory Medicine Department of Clinical Genetics and Pathology Skåne University Hospital Lund Sweden

Division of Molecular Hematology Lund Stem Cell Center Department of Laboratory Medicine Lund University Lund Sweden

Laboratory of Hematology Centre Hospitalier Universitaire Lille Lille France

Unité Mixte de Recherche en Santé 1172 INSERM University of Lille Lille France

Blood. 2020 Aug 20;136(8):919-920. doi: 10.1182/blood.2020006607. PubMed

Blood Adv. 2021 Apr 27;5(8):2075-2078. doi: 10.1182/bloodadvances.2020003643. PubMed

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