CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax

Cell Rep. 2023 Sep 26;42(9):113084. doi: 10.1016/j.celrep.2023.113084. Epub 2023 Sep 15.

Abstract

Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo, suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL.

Keywords: BCL2; CBFA2T3-GLIS2; CP: Cancer; ETO2-GLIS2; Ras; acute megakaryoblastic leukemia; apoptosis; mouse model; navitoclax; pediatric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds
  • Animals
  • Child
  • Humans
  • Leukemia, Megakaryoblastic, Acute* / drug therapy
  • Leukemia, Megakaryoblastic, Acute* / genetics
  • Mice
  • Oncogene Proteins, Fusion / metabolism
  • Repressor Proteins
  • Sulfonamides

Substances

  • navitoclax
  • Aniline Compounds
  • Sulfonamides
  • Oncogene Proteins, Fusion
  • CBFA2T3 protein, human
  • Repressor Proteins
  • CBFA2T3-GLIS2 fusion protein, human