Dataset Information

High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.

ABSTRACT: Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and cell death. Patient-derived ETO2::GLIS2⁺ leukemic cells expressed both high CASP3 and high BCL2. While BCL2 inhibition partly inhibited ETO2::GLIS2⁺ leukemic cell proliferation, BH3 profiling revealed that it also sensitized these cells to MCL1 inhibition indicating a functional redundancy between BCL2 and MCL1. We further show that combined inhibition of BCL2 and MCL1 is mandatory to abrogate disease progression using in vivo patient-derived xenograft models. These data reveal that a transcriptional consequence of ETO2::GLIS2 expression includes a positive regulation of the pro-apoptotic CASP3 and associates with a vulnerability to combined targeting of two BCL2 family members providing a novel therapeutic perspective for this aggressive pediatric AML subgroup.

SUBMITTER: Aid Z

PROVIDER: S-EPMC10583253 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.

Aid Zakia Z Robert Elie E Lopez Cécile K CK Bourgoin Maxence M Boudia Fabien F Le Mene Melchior M Riviere Julie J Baille Marie M Benbarche Salima S Renou Laurent L Fagnan Alexandre A Thirant Cécile C Federici Laetitia L Touchard Laure L Lecluse Yann Y Jetten Anton A Geoerger Birgit B Lapillonne Hélène H Solary Eric E Gaudry Muriel M Meshinchi Soheil S Pflumio Françoise F Auberger Patrick P Lobry Camille C Petit Arnaud A Jacquel Arnaud A Mercher Thomas T

Leukemia 20221230 3

Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and ...[more]

PMID: 36585521

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Project description:In the recent years, massively parallel sequencing approaches identified hundreds of mutated genes in cancer providing an unprecedented amount of information about mechanisms of cancer cell maintenance and progression. However, while (it is widely accepted that) transformation processes result from oncogenic cooperation between deregulated genes and pathways, the functional characterization of candidate key players is mostly performed at the single gene level which is generally inadequate to identify these oncogene circuitries. In addition, studies aimed at depicting oncogenic cooperation involve the generation of challenging mouse models or the deployment of tedious screening pipelines. Genome wide mapping of epigenomic modifications on histone tails or binding of factors such as MED1 and BRD4 allowed identification of clusters of regulatory elements, also termed Super-Enhancers (SE). Functional annotation of these regions revealed their high relevance during normal tissue development and cancer ontogeny. An interesting paradigm of the tumorigenic function of these SE regions comes from ETO2-GLIS2-driven acute megakaryoblastic leukemia (AMKL) in which the fusion protein ETO2-GLIS2 is sufficient to promote an aberrant transcriptional network by the rewiring of SE regions4. We thus hypothesized that important regulatory regions could control simultaneously expression of genes cooperating in functional modules to promote cancer development. In an effort to identify such modules, we deployed a genome-wide CRISPRi-based screening approach and nominated SE regions that are functionally linked to leukemia maintenance. In particular, we pinpointed a novel SE region regulating the expression of both tyrosine kinases KIT and PDGFRA. Whereas the inhibition of each kinase alone affected modestly cancer cell growth, combined inhibition of both receptors synergizes to impair leukemia cell growth and survival. Our results demonstrate that genome-wide screening of regulatory DNA elements can identify co-regulated genes collaborating to promote cancer and could open new avenues to the concept of combined gene inhibition upon single hit targeting.

Dataset Information

High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.

Publications

High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.

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