Article ; Online: CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax.
2023 Volume 42, Issue 9, Page(s) 113084
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 ... ...
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. |
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MeSH term(s) | Animals ; Mice ; Child ; Humans ; Leukemia, Megakaryoblastic, Acute/drug therapy ; Leukemia, Megakaryoblastic, Acute/genetics ; Aniline Compounds ; Sulfonamides ; Oncogene Proteins, Fusion/metabolism ; Repressor Proteins |
Chemical Substances | navitoclax (XKJ5VVK2WD) ; Aniline Compounds ; Sulfonamides ; Oncogene Proteins, Fusion ; CBFA2T3 protein, human ; Repressor Proteins ; CBFA2T3-GLIS2 fusion protein, human |
Language | English |
Publishing date | 2023-09-15 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2649101-1 |
ISSN | 2211-1247 ; 2211-1247 |
ISSN (online) | 2211-1247 |
ISSN | 2211-1247 |
DOI | 10.1016/j.celrep.2023.113084 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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