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

Michael Broux, Cristina Prieto, Sofie Demeyer, Marlies Vanden Bempt, Llucia Alberti-Servera, Inge Lodewijckx, Roel Vandepoel, Nicole Mentens, Olga Gielen, Kris Jacobs, Ellen Geerdens, Carmen Vicente, Charles de Bock and Jan Cools

Key Points

  • Suz12 inactivation cooperates with JAK3 mutant signaling to drive T-ALL development

  • JAK3/Suz12 mutant leukemia cells show increased sensitivity to PI3K/mTOR, VEGFR and HSP90 inhibitors


The PRC2 complex, with core components EZH2, SUZ12 and EED, is responsible for writing H3K27me3 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/mTOR, VEGF and WNT signaling. Moreover, a drug screen revealed that JAK3/Suz12 mutant leukemia cells were more sensitive to HDAC6 inhibition than JAK3 mutant leukemia cells. Among the broad genome and gene expression changes observed upon Suz12 inactivation, our integrated analysis identified the PI3K/mTOR, VEGF/VEGFR and HDAC6/HSP90 pathways as specific vulnerabilities in T-ALL cells with combined JAK3 and SUZ12 mutations.

  • Submitted February 1, 2019.
  • Revision received July 29, 2019.
  • Accepted August 26, 2019.