2. Academic Validation
  3. Suz12 inactivation cooperates with JAK3 mutant signaling in the development of T-cell acute lymphoblastic leukemia

Suz12 inactivation cooperates with JAK3 mutant signaling in the development of T-cell acute lymphoblastic leukemia

  • Blood. 2019 Oct 17;134(16):1323-1336. doi: 10.1182/blood.2019000015.
Michael Broux 1 2,  Cristina Prieto 1 2,  Sofie Demeyer 1 2,  Marlies Vanden Bempt 1 2,  Llucia Alberti-Servera 1 2,  Inge Lodewijckx 1 2,  Roel Vandepoel 1 2,  Nicole Mentens 1 2,  Olga Gielen 1 2,  Kris Jacobs 1 2,  Ellen Geerdens 1 2,  Carmen Vicente 3 4,  Charles E de Bock 1 2 5,  Jan Cools 1 2
Affiliations

Affiliations

  • 1 VIB Center for Cancer Biology, Leuven, Belgium.
  • 2 KU Leuven Center for Human Genetics, Leuven, Belgium.
  • 3 University of Navarra, Centro de Investigación Médica Aplicada, Pamplona, Spain.
  • 4 University of Navarra, Department of Biochemistry and Genetics, Pamplona, Spain; and.
  • 5 Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick, Australia.
PMID: 31492675 DOI: 10.1182/blood.2019000015
Abstract

The polycomb repressive complex 2, with core components EZH2, SUZ12, and EED, is responsible for writing histone 3 lysine 27 trimethylation histone marks associated with gene repression. Analysis of sequence data from 419 T-cell acute lymphoblastic leukemia (T-ALL) cases demonstrated a significant association between SUZ12 and JAK3 mutations. Here we show that CRISPR/Cas9-mediated inactivation of Suz12 cooperates with mutant JAK3 to drive T-cell transformation and T-ALL development. Gene expression profiling integrated with ChIP-seq and ATAC-seq data established that inactivation of Suz12 led to increased PI3K/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and Wnt signaling. Moreover, a drug screen revealed that JAK3/Suz12 mutant leukemia cells were more sensitive to histone deacetylase (HDAC)6 inhibition than JAK3 mutant leukemia cells. Among the broad genome and gene expression changes observed on Suz12 inactivation, our integrated analysis identified the PI3K/mTOR, VEGF/VEGF receptor, and HDAC6/HSP90 pathways as specific vulnerabilities in T-ALL cells with combined JAK3 and SUZ12 mutations.

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