GPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis
He X, Hawkins C, Lawley L, Phan T, Park I, Joven N, Zhang J, Wunderlich M, Mizukawa B, Pei S, Patel A, VanOudenhove J, Halene S, Fang J. GPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2024, 1871: 167565. PMID: 39522891, DOI: 10.1016/j.bbadis.2024.167565.Peer-Reviewed Original ResearchAcute myeloid leukemiaAcute myeloid leukemia cellsPro-survival pathwaysInhibiting isocitrate dehydrogenaseMetabolic symbiosisMyelodysplastic syndromeHematopoietic malignanciesExtracellular acidosisAssociated with inferior clinical outcomesCellular respirationFirst-line chemotherapeutic agentAcute myeloid leukemia patientsInferior clinical outcomesAerobic glycolysisCell survival in vitroEngraftment in vivoDecreased Ca<sup>2+</sup> levelDecreased aerobic glycolysisSurvival in vitroGlucose metabolic pathwaysG protein-coupled receptor 68Impacts chemosensitivityIn vitro observationsTumoricidal effectMyeloid leukemiaO6-Guanine Targeting Novel DNA Cross-Linker and ATR Inhibitor Combination for MGMT-Silenced IDH1/2 Mutant Acute Myeloid Leukemia
Bhardwaj P, Sundaram R, Friedman S, Baassiri A, Matthews M, VanOudenhove J, Gueble S, Halene S, Bindra R. O6-Guanine Targeting Novel DNA Cross-Linker and ATR Inhibitor Combination for MGMT-Silenced IDH1/2 Mutant Acute Myeloid Leukemia. Blood 2024, 144: 6130. DOI: 10.1182/blood-2024-210621.Peer-Reviewed Original ResearchAML patient samplesHematologic adverse effectsMGMT promoter hypermethylationPatient-derived xenograftsDe novoMismatch repairO6 position of guaninePromoter hypermethylationMyelodysplastic syndromeRNA-seq analysisMyeloid leukemiaATR inhibitorsDNA repair proteinsClinical trialsSelection of mutationsFunctional mismatch repairPatient samplesMutant acute myeloid leukemiaBiomarker-targeted therapiesCell line pairsAlkylation DNA damageMutant IDH1/2 inhibitorsRNA-seqCases of AMLMGMT promoter methylation