Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research
We further performed knockdown (KD) of BCL2L1 and NOTCH1 using lentiviral vectors in MV4-11 and HL60 AML cell lines. Apoptosis induction by VEN and/or DEC was measured by Annexin V flow cytometry. Silencing of BCL2L1 was associated with higher apoptosis induction by VEN and/or DEC treatment compared to control vector-transfected cells in both MV4;11 and HL60, with more pronounced effects in MV4-11 (% increase in specific apoptosis compared to control; MV4;11: VEN 25.5±0.6%, DEC 11.5±0.2%, VEN+DEC 40.5±0.4%, HL60: VEN 6.1±1.6%, DEC 9.1±1.1%, VEN-DEC 13.7±0.8%). In contrast, NOTCH1 KD did not impact apoptosis induction after exposure to DEC and/or VEN compared to control cells in both cell lines. Notably, however, in both MV4;11 and HL 60 cells, VEN-induced apoptosis was enhanced by BCL2L1/NOTCH1 double KD compared to BCL2L1 only KD (MV4;11: 31.4±1.7%, HL60: 21.5±3.0%).
In summary, we propose here a predictive model for VEN-DEC treatment resistance that encompasses BCL2L1, a pro-survival and VEN resistance factor; and NOTCH1 and NRIP1, which are involved in control of the quiescent state in LSCs. Further studies are needed to determine the contribution of NOTCH1 and NRIP1 to proliferation and differentiation of AML LSCs. While these putative resistance markers need further validation in larger studies, we hypothesize that combined inhibition of BCL-xL and of Notch1 signaling may induce apoptosis and eradiate VEN-resistant quiescent LSCs.
Disclosures: Maiti: Inspirna: Research Funding; Lin Biosciences: Research Funding; Hibercell Inc.: Research Funding; CytoMed Therapeutics: Research Funding; Chimeric Therapeutics: Research Funding; Indapta Therapeutics: Research Funding. DiNardo: Foghorn: Research Funding; Astellas: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; GSK: Consultancy, Honoraria; Stemline: Consultancy; Immunogen: Honoraria; Loxo: Research Funding; Astex: Research Funding; Cleave: Research Funding; Jazz: Consultancy, Honoraria; Gilead: Consultancy; Schrodinger: Consultancy, Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Notable Labs: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy; Rigel: Research Funding; ImmuneOnc: Research Funding; Riegel: Honoraria; Genetech: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria. Andreeff: Paraza: Honoraria; Sellas: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Eterna: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Syndax: Honoraria, Research Funding; Ona: Honoraria; Oncolyze: Current holder of stock options in a privately-held company; Boehringer-Ingelheim: Honoraria; Glycomimetics: Honoraria; Kintor Pharmaceutical: Research Funding; Oxford Biomedical: Research Funding; Ellipses: Research Funding; SentiBio: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Aptose: Honoraria; Chimerix: Current holder of stock options in a privately-held company; Roivant: Honoraria. Abbas: Enzyme By Design: Research Funding; Ascentage: Research Funding; Alamar Biosciences: Honoraria; Illumina: Honoraria, Other: Inkind Support, Research Funding; GlaxoSmithKline: Research Funding; Blueprint Medicines Corporation: Research Funding; Molecular Partners: Consultancy; Genentech: Research Funding. Konopleva: Curis: Consultancy; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Intellisphere: Speakers Bureau; Sanofi Aventis: Consultancy; Servier: Speakers Bureau; Klondike Biopharma: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Other: clinical trials; Vincerx: Consultancy; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy.
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