Featured Publications
BTG1 mutation yields supercompetitive B cells primed for malignant transformation
Mlynarczyk C, Teater M, Pae J, Chin C, Wang L, Arulraj T, Barisic D, Papin A, Hoehn K, Kots E, Ersching J, Bandyopadhyay A, Barin E, Poh H, Evans C, Chadburn A, Chen Z, Shen H, Isles H, Pelzer B, Tsialta I, Doane A, Geng H, Rehman M, Melnick J, Morgan W, Nguyen D, Elemento O, Kharas M, Jaffrey S, Scott D, Khelashvili G, Meyer-Hermann M, Victora G, Melnick A. BTG1 mutation yields supercompetitive B cells primed for malignant transformation. Science 2023, 379: eabj7412. PMID: 36656933, PMCID: PMC10515739, DOI: 10.1126/science.abj7412.Peer-Reviewed Original ResearchConceptsGerminal center B cellsPositive selection signalsB-cell fitnessCell fitnessUnicellular organismsB cellsMulticellular lifeNatural selectionSelection signalsInduction kineticsGatekeeper mechanismAdaptive immune systemAltruistic cooperationNew mouse modelNormal counterpartsHuman lymphomasAntibody affinity maturationCellsInvasive lymphomaClinical outcomesMouse modelImmune systemMalignant transformationSupercompetitorsAffinity maturationCyclin D3 drives inertial cell cycling in dark zone germinal center B cells
Pae J, Ersching J, Castro T, Schips M, Mesin L, Allon S, Ordovas-Montanes J, Mlynarczyk C, Melnick A, Efeyan A, Shalek A, Meyer-Hermann M, Victora G. Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells. Journal Of Experimental Medicine 2020, 218: e20201699. PMID: 33332554, PMCID: PMC7754672, DOI: 10.1084/jem.20201699.Peer-Reviewed Original ResearchConceptsGC B cellsB cellsGerminal centersExpansion of GC B cellsDose-dependentlyClonal B-cell lymphoproliferationGerminal center B cellsB-cell lymphoproliferationCyclin D3Gain-of-function mutationsCell cycle regulator cyclin D3Cell cycle programAffinity-dependent selectionLight zoneMalignant transformationClonal expansionOld miceVigorous proliferationCell cycleSomatic hypermutationCCND3 genesAffinity maturationDark zoneProliferationCyclinGerminal center‐derived lymphomas: The darkest side of humoral immunity
Mlynarczyk C, Fontán L, Melnick A. Germinal center‐derived lymphomas: The darkest side of humoral immunity. Immunological Reviews 2019, 288: 214-239. PMID: 30874354, PMCID: PMC6518944, DOI: 10.1111/imr.12755.Peer-Reviewed Original ResearchConceptsB cellsGC reactionGerminal centersImmune receptor signalingBCL6 transcription factorTreated lymphoma patientsB-cell neoplasmsFunction of BCL6GC-derived lymphomasImmune regulatory mechanismsMutations of genesGC B cellsClonal diversityTranscription factorsBiological themesEpigenetic regulationGenomic lesionsPoint mutationsRegulatory mechanismsEpigenetic programmingLymphoma patientsOncogenic functionEpigenetic standpointTumor-suppressive effectsMutationsEndoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21CDKN1A
Mlynarczyk C, Fåhraeus R. Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21CDKN1A. Nature Communications 2014, 5: 5067. PMID: 25295585, DOI: 10.1038/ncomms6067.Peer-Reviewed Original ResearchConceptsCells to DNA damage-induced apoptosisER stressEndoplasmic reticulumDNA damage-induced apoptosisP53-dependent induction of p21G2 arrestDamage-induced apoptosisP53-induced apoptosisP53-dependent inductionDNA damageInduction of p21Endoplasmic reticulum stressCell cycle coordinationPromote G2 arrestP21 transcriptionP53 isoformsMRNA translationP53 pathwayG1 arrestGenotoxic drugsG2 checkpointReticulum stressSuppressing p21P53/47P53
2024
Tuning Responses to Polatuzumab Vedotin in B-cell Lymphoma.
Leveille E, Kothari S, Cosgun K, Mlynarczyk C, Müschen M. Tuning Responses to Polatuzumab Vedotin in B-cell Lymphoma. Cancer Discovery 2024, 14: 1577-1580. PMID: 39228298, DOI: 10.1158/2159-8290.cd-24-0644.Peer-Reviewed Original ResearchARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis
Barisic D, Chin C, Meydan C, Teater M, Tsialta I, Mlynarczyk C, Chadburn A, Wang X, Sarkozy M, Xia M, Carson S, Raggiri S, Debek S, Pelzer B, Durmaz C, Deng Q, Lakra P, Rivas M, Steidl C, Scott D, Weng A, Mason C, Green M, Melnick A. ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis. Cancer Cell 2024, 42: 583-604.e11. PMID: 38458187, PMCID: PMC11407687, DOI: 10.1016/j.ccell.2024.02.010.Peer-Reviewed Original ResearchConceptsFollicular lymphomaGerminal centersB cell fateAggressive follicular lymphomasMemory B cellsHigh-risk patientsSequential bindingNucleosome remodeling complexAggressive diseaseARID1A mutationsBinding of PUClonal precursorsBCL2 oncogeneB cellsPrecision therapyARID1ACD40 signalingLymphomaARID1A inactivationNF-kBRemodeling complexCell fateTranscription factorsPatientsMutations
2022
Conformational transitions in BTG1 antiproliferative protein and their modulation by disease mutants
Kots E, Mlynarczyk C, Melnick A, Khelashvili G. Conformational transitions in BTG1 antiproliferative protein and their modulation by disease mutants. Biophysical Journal 2022, 121: 3753-3764. PMID: 35459639, PMCID: PMC9617077, DOI: 10.1016/j.bpj.2022.04.023.Peer-Reviewed Original ResearchConceptsB-cell translocation gene 1Antiproliferative proteinAssociate with transcriptional cofactorsFamily of antiproliferative proteinsWild-typeFunctional interactionsDisease-linked mutationsSomatic missense mutationsCell cycle progressionMarkov state model analysisConformational transitionBinding partnersTranscriptional cofactorCellular partnersCellular processesProtein regionsDisease mutantsMissense mutationsCycle progressionBinding hotspotsBinding proteinFunctional associationEnsemble of conformationsMolecular mechanismsA2-A4
2018
In Vivo Imaging With Confirmation by Histopathology for Increased Rigor and Reproducibility in Translational Research: A Review of Examples, Options, and Resources.
Gabrielson K, Maronpot R, Monette S, Mlynarczyk C, Ramot Y, Nyska A, Sysa-Shah P. In Vivo Imaging With Confirmation by Histopathology for Increased Rigor and Reproducibility in Translational Research: A Review of Examples, Options, and Resources. ILAR Journal 2018, 59: 80-98. PMID: 30541081, PMCID: PMC6645176, DOI: 10.1093/ilar/ily010.Peer-Reviewed Original ResearchConceptsAnimal modelsComprehensive pathological evaluationPreclinical animal modelsIn vivo imagingAnimal models of diseaseNoninvasive in vivo imaging methodsPathological evaluationModels of diseaseStandard histopathologyImaging confirmationMicroscopic morphological featuresNoninvasive imagingHistopathology
2010
Endoplasmic Reticulum Stress Induces G2 Cell-Cycle Arrest via mRNA Translation of the p53 Isoform p53/47
Bourougaa K, Naski N, Boularan C, Mlynarczyk C, Candeias M, Marullo S, Fåhraeus R. Endoplasmic Reticulum Stress Induces G2 Cell-Cycle Arrest via mRNA Translation of the p53 Isoform p53/47. Molecular Cell 2010, 38: 78-88. PMID: 20385091, DOI: 10.1016/j.molcel.2010.01.041.Peer-Reviewed Original ResearchConceptsMRNA translationOutcome of p53 activationTrans-activation domainP53 downstream pathwaysMDM2 binding siteG2 cell cycle arrestCell cycle arrestEndoplasmic reticulum stressP53 isoformsP53/47P53 activationHomo-oligomerizationP53 pathwayG1 progressionTrans-activationCellular stressDNA repairG1 arrestBiochemical propertiesG2 arrestReticulum stressResponse to different typesDownstream pathwaysAmino acidsP53