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 methylationClonal Dissection of MDS and Secondary AML Resolves Shared Splicing Neoantigens and Mechanistic Underpinnings of Hypomethylating Agent Therapeutic Response
Zhang X, Li G, Oliverio A, VanOudenhove J, DeZern A, Ghiaur G, Halene S, Grimes H, Salomonis N. Clonal Dissection of MDS and Secondary AML Resolves Shared Splicing Neoantigens and Mechanistic Underpinnings of Hypomethylating Agent Therapeutic Response. Blood 2024, 144: 1810-1810. DOI: 10.1182/blood-2024-211099.Peer-Reviewed Original ResearchHematopoietic stem cellsHypomethylating agent therapyHypomethylating agentsMyelodysplastic syndromeSecondary AMLBone marrow hematopoietic stem cellsHigh-risk myelodysplastic syndromeQuiescent hematopoietic stem cellsMarrow hematopoietic stem cellsSplicing alterationsPrimary myelodysplastic syndromesMyelodysplastic syndrome patientsGene programHeterogeneous hematological disorderMDS therapyAged bone marrowAssociated with down-regulationHuman hematopoietic progenitorsSingle-cell populationsAssociated with mutationsSurface protein expressionGene expressionCell statesIllumina short readsPrimitive HSCsUnraveling the Drivers of the Stress Granule Signature in Splicing Factor-Mutant Myeloid Malignancies
Biancon G, Busarello E, Cheng M, Sidoli S, VanOudenhove J, Bucciarelli G, Tebaldi T, Halene S. Unraveling the Drivers of the Stress Granule Signature in Splicing Factor-Mutant Myeloid Malignancies. Blood 2024, 144: 4117. DOI: 10.1182/blood-2024-211265.Peer-Reviewed Original ResearchRNA-binding proteinsStress granulesRNA-seqArsenite stressSF mutationsAcute myeloid leukemiaSplicing factorsSG proteinsStress responseClonal advantageSG coresMulti-omicsDeregulated genesMyelodysplastic syndromeEnhances SG formationU2AF1 S34F mutationSingle-cell RNA-seqWT cellsMegakaryocyte-erythroid progenitorsRegulation of translationTranslation initiation factorsImprove cell fitnessRNA-seq analysisPost-translational modificationsU2AF1 mutationsMISTRG6kitW41: Enhanced Engraftment in a Cytokine Humanized Patient-Derived Xenotransplantation Mouse Model
Baassiri A, Maziarz J, Blackburn H, Maul-Newby H, VanOudenhove J, Zhang X, Matthews M, Paul S, Liu W, Sefik E, Salomonis N, Grimes H, Flavell R, Halene S. MISTRG6kitW41: Enhanced Engraftment in a Cytokine Humanized Patient-Derived Xenotransplantation Mouse Model. Blood 2024, 144: 1815-1815. DOI: 10.1182/blood-2024-211908.Peer-Reviewed Original ResearchPeripheral blood-mobilized stem cellsAcute myeloid leukemiaProgression to secondary acute myeloid leukemiaHematopoietic stem cellsWeeks post-engraftmentSecondary acute myeloid leukemiaStudies of myelodysplastic syndromesMyelodysplastic syndromeCD34+ cellsEngraftment levelsPeripheral bloodBone marrowK micePost-engraftmentMouse modelNSG miceMDS samplesEngraftment of human hematopoietic stem cellsEnhanced engraftmentProgression to acute myeloid leukemiaHealthy donor peripheral bloodHuman CD45+ cellsHuman hematopoietic stem cellsAnalysis of CD34+ cellsPercentage of lymphoid cells