2024
P-088 Evaluating T-cell Fitness Pre B-Cell Maturation Antigen (BCMA)-Targeted T-Cell Redirection Therapies (TRT) as a Predictive Marker for Efficacy/Toxicity in Relapsed/Refractory Multiple Myeloma (RRMM)
Theprungsirikul P, Yu M, Liu Y, Rall K, Matthews M, Neparidze N, Parker T, Browning S, Anderson T, Stevens E, Foss F, Gowda L, Pillai M, Isufi I, Seropian S, Mirza S, Bar N. P-088 Evaluating T-cell Fitness Pre B-Cell Maturation Antigen (BCMA)-Targeted T-Cell Redirection Therapies (TRT) as a Predictive Marker for Efficacy/Toxicity in Relapsed/Refractory Multiple Myeloma (RRMM). Clinical Lymphoma Myeloma & Leukemia 2024, 24: s92-s93. DOI: 10.1016/s2152-2650(24)01991-8.Peer-Reviewed Original ResearchAssociations of T-cell fitness prior to B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T-cell (CART) and bispecific T-cell engager (BiTE) therapies and efficacy/toxicity in relapsed/refractory multiple myeloma (RRMM).
Theprungsirikul P, Yu M, Rall K, Matthews M, Neparidze N, Parker T, Browning S, Anderson T, Stevens E, Foss F, Gowda L, Pillai M, Isufi I, Seropian S, Mirza S, Bar N. Associations of T-cell fitness prior to B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T-cell (CART) and bispecific T-cell engager (BiTE) therapies and efficacy/toxicity in relapsed/refractory multiple myeloma (RRMM). Journal Of Clinical Oncology 2024, 42: 7549-7549. DOI: 10.1200/jco.2024.42.16_suppl.7549.Peer-Reviewed Original ResearchChimeric antigen receptor T cellsRelapsed/refractory multiple myelomaT cell fitnessHigh-risk cytogeneticsCytokine release syndromeNon-respondersExtramedullary diseaseT cellsPeripheral blood prior to treatmentInternational Myeloma Working Group criteriaNR groupBlood prior to treatmentBispecific T-cell engagerMedian follow-up timeMedian prior linesT-cell therapyPost-treatment follow-upT-cell engagersT cell influxT-cell %Working Group criteriaYale Cancer CenterMann-Whitney U testResponse to disease progressionIdecabtagene vicleucelTranscription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape
Boddu P, Gupta A, Roy R, De La Peña Avalos B, Olazabal-Herrero A, Neuenkirchen N, Zimmer J, Chandhok N, King D, Nannya Y, Ogawa S, Lin H, Simon M, Dray E, Kupfer G, Verma A, Neugebauer K, Pillai M. Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape. Molecular Cell 2024, 84: 1475-1495.e18. PMID: 38521065, PMCID: PMC11061666, DOI: 10.1016/j.molcel.2024.02.032.Peer-Reviewed Original ResearchRate of RNA polymerase IIChromatin landscapeElongation defectsElongation rate of RNA polymerase IIImpaired protein-protein interactionsSplicing of pre-messenger RNATranscription elongation defectsRNA polymerase IIProtein-protein interactionsPre-messenger RNACancer-associated mutationsIsogenic cell linesSin3/HDAC complexGene bodiesPolymerase IIChromatin accessibilityH3K4me3 markChromatin changesMutant SF3B1ChromatinMutant mouse modelsEpigenetic disordersEpigenetic factorsHuman diseasesMutant statePD-1H/VISTA mediates immune evasion in acute myeloid leukemia
Kim T, Han X, Hu Q, Vandsemb E, Fielder C, Hong J, Kim K, Mason E, Plowman R, Wang J, Wang Q, Zhang J, Badri T, Sanmamed M, Zheng L, Zhang T, Alawa J, Lee S, Zeidan A, Halene S, Pillai M, Chandhok N, Lu J, Xu M, Gore S, Chen L. PD-1H/VISTA mediates immune evasion in acute myeloid leukemia. Journal Of Clinical Investigation 2024, 134 PMID: 38060328, PMCID: PMC10836799, DOI: 10.1172/jci164325.Peer-Reviewed Original ResearchThe FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export
Olazabal-Herrero A, He B, Kwon Y, Gupta A, Dutta A, Huang Y, Boddu P, Liang Z, Liang F, Teng Y, Lan L, Chen X, Pei H, Pillai M, Sung P, Kupfer G. The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export. Cell Reports 2024, 43: 113610. PMID: 38165804, PMCID: PMC10865995, DOI: 10.1016/j.celrep.2023.113610.Peer-Reviewed Original Research
2023
Impaired Early Spliceosome Complex Assembly Underlies Gene Body Elongation Transcription Defect in SF3B1K700E
Boddu P, Gupta A, Roy R, De La Pena Avalos B, Herrero A, Zimmer J, Simon M, Chandhok N, King D, Neuenkirchen N, Dray E, Lin H, Kupfer G, Verma A, Neugebauer K, Pillai M. Impaired Early Spliceosome Complex Assembly Underlies Gene Body Elongation Transcription Defect in SF3B1K700E. Blood 2023, 142: 714. DOI: 10.1182/blood-2023-187303.Peer-Reviewed Original ResearchSplicing factorsChIP-seqK562 cell lineKey regulatory genesCell linesSingle mutant alleleNon-denaturing gelsAlternative splicingTranscriptional kineticsRegulatory genesSpliceosome assemblySplicing efficiencyMRNA splicingCRISPR/Progenitor populationsNeomorphic functionsMolecular mechanismsMutant allelesIsoform changesGene editingNovel mechanismMutationsSF mutationsRecurrent mutationsAssembly kineticsTranscription Defects in SF3B1K700E Induce Targetable Alterations in the Chromatin Landscape
Boddu P, Gupta A, Roy R, Herrero A, Verma A, Neugebauer K, Pillai M. Transcription Defects in SF3B1K700E Induce Targetable Alterations in the Chromatin Landscape. Blood 2023, 142: 709. DOI: 10.1182/blood-2023-188083.Peer-Reviewed Original ResearchChromatin organizationSuch epigenetic changesGenome editing approachesRNA splicing factorsChromatin landscapeSingle mutant alleleEpigenetic landscapeGenomic integrityTranscription defectTranscription kineticsSplicing factorsChIP-seqEpigenetic regulatorsEpigenetic changesEpigenetic therapyMutant allelesEditing approachesFactor mutationsK562 cell lineDownstream effectsCell linesMyeloid disordersClonal myeloid disordersHDAC pathwayMutations
2022
Complex Formation between FANCD2 and the Splicing Factor SRSF1 Helps Prevent R-Loop Accumulation through mRNA Export Regulation
Herrero A, Liang F, Dutta A, Huang Y, Liang Z, Gupta A, Lan L, Pillai M, Sung P, Kupfer G. Complex Formation between FANCD2 and the Splicing Factor SRSF1 Helps Prevent R-Loop Accumulation through mRNA Export Regulation. Blood 2022, 140: 5828-5829. DOI: 10.1182/blood-2022-166798.Peer-Reviewed Original ResearchActivation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
Choudhary GS, Pellagatti A, Agianian B, Smith MA, Bhagat TD, Gordon-Mitchell S, Sahu S, Pandey S, Shah N, Aluri S, Aggarwal R, Aminov S, Schwartz L, Steeples V, Booher RN, Ramachandra M, Samson M, Carbajal M, Pradhan K, Bowman TV, Pillai MM, Will B, Wickrema A, Shastri A, Bradley RK, Martell RE, Steidl UG, Gavathiotis E, Boultwood J, Starczynowski DT, Verma A. Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations. ELife 2022, 11: e78136. PMID: 36040792, PMCID: PMC9427103, DOI: 10.7554/elife.78136.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaMyelodysplastic syndromeNF-kB activationLymphoma SocietyMDS/acute myeloid leukemiaNational InstitutePathogenesis of MDSInterleukin-1 receptor-associated kinase 4Expression of IRAK4Inflammatory-immune pathwaysInflammatory cytokine productionSpecific oncogenic pathwaysCareer development grantsHealth research trainingCritical downstream mediatorCytokine productionMyeloid leukemiaPreclinical modelsNew York State DepartmentXenograft modelImmune pathwaysNF-kB.MDS samplesTRAF6 activationLeukemic growthIntegrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)
Karmakar S, Ramirez O, Paul KV, Gupta AK, Kumari V, Botti V, de los Mozos IR, Neuenkirchen N, Ross RJ, Karanicolas J, Neugebauer KM, Pillai MM. Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2). NAR Cancer 2022, 4: zcac015. PMID: 35528200, PMCID: PMC9070473, DOI: 10.1093/narcan/zcac015.Peer-Reviewed Original ResearchRNA binding proteinMusashi-2Functional targetIntegrative genome-wide analysisGenome-wide analysisIndividual-nucleotide resolutionAsymmetric cell divisionCell fate decisionsThousands of mRNAsKey downstream regulatorProtein Musashi-2Polysome profilingFate decisionsEukaryotic translation initiation factor 3aNucleotide resolutionCell divisionDirect RNATranslational inductionCancer stem cellsDownstream regulatorsUntranslated regionIndirect targetsBinding proteinDirect targetMere binding
2021
Fanci-FANCD2 Promotes Genome Stability and DNA Repair By Down-Regulating BLM Helicase Activity
Liang F, Nagarajan A, Pillai M, Sung P, Kupfer G. Fanci-FANCD2 Promotes Genome Stability and DNA Repair By Down-Regulating BLM Helicase Activity. Blood 2021, 138: 1113. DOI: 10.1182/blood-2021-152218.Peer-Reviewed Original ResearchDNA end resectionReplication forksGenome stabilityDNA repairResection activityRAD51 recruitmentEnd resectionAmino acid deletionBloom syndromeFanconi anemiaMutant cellsFA DNA repair pathwayAcid deletionDNA damageDNA damage hypersensitivityReplication fork collapseBLM helicase activityEfficient DNA repairHolliday junction dissolutionDNA damage repairDNA repair pathwaysRAD51 foci formationDouble Holliday junction dissolutionIsolation of proteinsHU sensitivityGeneration of scalable cancer models by combining AAV-intron-trap, CRISPR/Cas9, and inducible Cre-recombinase
Boddu PC, Gupta AK, Kim JS, Neugebauer KM, Waldman T, Pillai MM. Generation of scalable cancer models by combining AAV-intron-trap, CRISPR/Cas9, and inducible Cre-recombinase. Communications Biology 2021, 4: 1184. PMID: 34645977, PMCID: PMC8514589, DOI: 10.1038/s42003-021-02690-1.Peer-Reviewed Original Research40008 COMBINED CRISPR/CAS9 AND AAV FOR THE GENERATION OF CONDITIONAL ISOGENIC GENE KNOCK-INS
Boddu P, Gupta A, Waldman T, Pillai M. 40008 COMBINED CRISPR/CAS9 AND AAV FOR THE GENERATION OF CONDITIONAL ISOGENIC GENE KNOCK-INS. Journal Of Clinical And Translational Science 2021, 5: 22-22. PMCID: PMC8827824, DOI: 10.1017/cts.2021.460.Peer-Reviewed Original ResearchChallenges in the Evaluation and Management of Toxicities Arising From Immune Checkpoint Inhibitor Therapy for Patients With Myeloid Malignancies
Shallis RM, Bewersdorf JP, Swoboda DM, Wei W, Gowda L, Prebet T, Halene S, Pillai MM, Parker T, Neparidze N, Podoltsev NA, Seropian S, Sallman DA, Gore SD, Zeidan AM. Challenges in the Evaluation and Management of Toxicities Arising From Immune Checkpoint Inhibitor Therapy for Patients With Myeloid Malignancies. Clinical Lymphoma Myeloma & Leukemia 2021, 21: e483-e487. PMID: 33551344, DOI: 10.1016/j.clml.2021.01.003.Peer-Reviewed Original Research
2020
Binding of FANCD2 to SRSF1 Splicing Factor Prevents Genomic Instability through R Loop Regulation
Olazabal-Herrero A, Green A, Chen X, Sung P, Pillai M, Kupfer G. Binding of FANCD2 to SRSF1 Splicing Factor Prevents Genomic Instability through R Loop Regulation. Blood 2020, 136: 19. DOI: 10.1182/blood-2020-141369.Peer-Reviewed Original ResearchR-loopsFA pathwayGenomic instabilityFanconi anemiaSplicing factorsR-loop metabolismR-loop regulationFA-like phenotypeBasic cellular processesR-loop formationKey regulatory stepNon-canonical roleDNA damaging agentsNon-canonical mechanismFANCD2-FANCIGenome maintenanceFANCD2 monoubiquitinationMRNA exportGenomic sitesCellular processesInsect cellsProcessing proteinsFA phenotypeRNA transcriptionRegulatory stepMulti-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells
Marczyk M, Patwardhan GA, Zhao J, Qu R, Li X, Wali VB, Gupta AK, Pillai MM, Kluger Y, Yan Q, Hatzis C, Pusztai L, Gunasekharan V. Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells. Cancers 2020, 12: 2551. PMID: 32911681, PMCID: PMC7563413, DOI: 10.3390/cancers12092551.Peer-Reviewed Original ResearchTriple-negative breast cancer cellsCancer cellsBreast cancer cellsStress response genesMulti-omics landscapeCell population compositionDrug-induced cell deathMulti-omics investigationsCell linesBCL2 family inhibitorsSingle-cell analysisChromatin accessibilityGenome structureMDA-MB-231 triple-negative breast cancer cellsChromatin structureMethylation stateResponse genesFamily inhibitorsCell deathTNBC cell linesNumber variationsDefense mechanismsResistance mechanismsNew therapeutic strategiesGenesClinical outcomes and characteristics of patients with TP53-mutated acute myeloid leukemia or myelodysplastic syndromes: a single center experience*
Bewersdorf JP, Shallis RM, Gowda L, Wei W, Hager K, Isufi I, Kim TK, Pillai MM, Seropian S, Podoltsev NA, Gore SD, Siddon AJ, Zeidan AM. Clinical outcomes and characteristics of patients with TP53-mutated acute myeloid leukemia or myelodysplastic syndromes: a single center experience*. Leukemia & Lymphoma 2020, 61: 2180-2190. PMID: 32362171, PMCID: PMC7603787, DOI: 10.1080/10428194.2020.1759051.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaMedian overall survivalTherapy-related malignanciesOverall survivalMyelodysplastic syndromeMyeloid leukemiaAllogeneic hematopoietic stem cell transplantLonger median overall survivalSingle-center retrospective studyComplex karyotypeHematopoietic stem cell transplantIntensive chemotherapy approachesYale Cancer CenterCharacteristics of patientsSingle-center experienceMinority of patientsStem cell transplantLong-term survivalLow response rateIntensive chemotherapyCenter experienceClinicopathologic characteristicsAdverse prognosisAML patientsCell transplant
2019
SF3B1 Mutations Induce Oncogenic IRAK4 Isoforms and Activate Targetable Innate Immune Pathways in MDS and AML
Choudhary G, Smith M, Pellagatti A, Bhagat T, Gordon S, Pandey S, Shah N, Aluri S, Booher R, Ramachandra M, Samson M, Pradhan K, Bowman T, Pillai M, Guha C, Wickrema A, Will B, Shastri A, Steidl U, Boultwood J, Starczynowski D, Verma A. SF3B1 Mutations Induce Oncogenic IRAK4 Isoforms and Activate Targetable Innate Immune Pathways in MDS and AML. Blood 2019, 134: 4224. DOI: 10.1182/blood-2019-124458.Peer-Reviewed Original ResearchToll-like receptorsAML cellsSF3B1 mutationsMDS/AML cellsInterleukin-1 Receptor-Associated KinaseMDS/AMLNF-kB activityInnate immune pathwaysInnate immune signalingNormal cellsDownstream oncogenic pathwaysLeukemic burdenCytokine releaseIRAK4 expressionNF-kBAML samplesImmune pathwaysSmall molecule inhibitorsNovartis PharmaceuticalsLeukemic cellsExon 6Mutation showTRAF6 activationAMLPharmacologic inhibitionAllogeneic Stem Cell Transplantation for T-Cell Lymphomas in the Modern Era: A Single Center Experience
Boddu P, Perreault S, Isufi I, Chandhok N, Kim T, Pillai M, Bar N, Prebet T, Zeidan A, Zelterman D, Seropian S, Gowda L, Foss F. Allogeneic Stem Cell Transplantation for T-Cell Lymphomas in the Modern Era: A Single Center Experience. Transplantation And Cellular Therapy 2019, 25: s387. DOI: 10.1016/j.bbmt.2018.12.796.Peer-Reviewed Original ResearchT-cell lymphomaProgression-free survivalTransplant related mortalityCumulative incidenceOverall survivalAutologous stem cell transplant consolidationOne-year progression-free survivalT-cell-rich B-cellT-cell lymphoma typesCutaneous T-cell lymphomaLong-term prospective studiesT-cell lymphoma subtypesPost-transplant relapseReduced intensity regimensTBI/CYHigh-dose chemotherapyNK T cellsSingle-center experienceOverall favorable outcomeKaplan-Meier analysisPretransplant conditioning regimenAllogeneic stem cellsPeripheral T-cell lymphoma subtypesAutologous SCTChronic GVHD
2017
Fibroblast Subtypes Regulate Responsiveness of Luminal Breast Cancer to Estrogen
Brechbuhl HM, Finlay-Schultz J, Yamamoto T, Gillen A, Cittelly DM, Tan AC, Sams SB, Pillai M, Elias A, Robinson WA, Sartorius CA, Kabos P. Fibroblast Subtypes Regulate Responsiveness of Luminal Breast Cancer to Estrogen. Clinical Cancer Research 2017, 23: 1710-1721. PMID: 27702820, PMCID: PMC5378660, DOI: 10.1158/1078-0432.ccr-15-2851.Peer-Reviewed Original ResearchConceptsCancer-associated fibroblastsBreast cancer cellsBreast cancerER expressionPatient outcomesCancer cellsEstrogen receptor-positive breast cancerReceptor-positive breast cancerTamoxifen-resistant breast cancer cellsBreast cancer-associated fibroblastsInferior clinical responseMajor clinical complicationsER expression levelsEstrogen-dependent proliferationWorse patient outcomesClin Cancer ResPatient breast tumorsTumor cell sensitivityTumor cell resistanceAntiendocrine therapyTamoxifen therapyClinical responseDisease recurrenceClinical complicationsDevelopment of resistance