{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T02:39:05Z","timestamp":1789871945405,"version":"4.0.1"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model; here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative\/Sca1+\/KIT+ (LSK) cells. Secondary transplants showed increased survival in treated compared to untreated mice. Unlike the AML model, BCL-2 expression and RAS activity decreased following treatment and the RAS:BCL-2 complex remained in the plasma membrane. Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regulation of stem cells, differentiation, proliferation, oxidative phosphorylation, mitochondrial function, and apoptosis; relevant in human disease. Spliceosome genes, found to be abnormal in MDS patients and downregulated in our HR-MDS model, such as Rsrc1 and Wbp4, were upregulated by the treatment, as were genes involved in epigenetic regulation, such as DNMT3A and B, upregulated upon disease progression and downregulated upon treatment.<\/jats:p>","DOI":"10.3390\/ijms221910658","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T10:55:40Z","timestamp":1633085740000},"page":"10658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS\/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome"],"prefix":"10.3390","volume":"22","author":[{"given":"Petra","family":"Gorombei","sequence":"first","affiliation":[{"name":"INSERM UMR-S1131, Universit\u00e9 de Paris, Institut de la Recherche Saint-Louis, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Saint-Louis H\u00f4pital, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1380-4473","authenticated-orcid":false,"given":"Fabien","family":"Guidez","sequence":"additional","affiliation":[{"name":"INSERM UMR-S1131, Universit\u00e9 de Paris, Institut de la Recherche Saint-Louis, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Saint-Louis H\u00f4pital, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saravanan","family":"Ganesan","sequence":"additional","affiliation":[{"name":"INSERM UMR-S1131, Universit\u00e9 de Paris, Institut de la Recherche Saint-Louis, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Saint-Louis H\u00f4pital, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Chiquet","sequence":"additional","affiliation":[{"name":"INSERM UMR-S1131, Universit\u00e9 de Paris, Institut de la Recherche Saint-Louis, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Saint-Louis H\u00f4pital, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6122-0221","authenticated-orcid":false,"given":"Andrea","family":"Pellagatti","sequence":"additional","affiliation":[{"name":"Blood Cancer UK Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and BRC Haematology Theme, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Goursaud","sequence":"additional","affiliation":[{"name":"INSERM UMR-S1131, Universit\u00e9 de Paris, Institut de la Recherche Saint-Louis, Assistance 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