2023
Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia
Chen Z, Zhou K, Xue J, Small A, Xiao G, Nguyen L, Zhang Z, Prince E, Weng H, Huang H, Zhao Z, Qing Y, Shen C, Li W, Han L, Tan B, Su R, Qin H, Li Y, Wu D, Gu Z, Ngo V, He X, Chao J, Leung K, Wang K, Dong L, Qin X, Cai Z, Sheng Y, Chen Y, Wu X, Zhang B, Shi Y, Marcucci G, Qian Z, Xu M, Müschen M, Chen J, Deng X. Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia. Science Translational Medicine 2023, 15: eabq8513. PMID: 36989375, PMCID: PMC11163962, DOI: 10.1126/scitranslmed.abq8513.Peer-Reviewed Original ResearchConceptsB-cell acute lymphoblastic leukemiaCell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaB-ALLRefractory/Oncogenic roleLymphoblastic leukemiaProtein kinase C epsilonOverall survival rateNormal precursor B cellsCrucial oncogenic rolePrecursor B cellsAdult patientsPDX modelsPharmacological targetingTherapeutic targetB cellsImproved therapiesSurvival rateLeukemia progressionTherapeutic potentialOverexpression of TET1TET1 proteinATM serine/threonine kinaseLeukemia
2021
PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
Pan L, Hong C, Chan LN, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras T, Wang S, Wajapeyee N, Müschen M. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2016553118. PMID: 33531346, PMCID: PMC7896313, DOI: 10.1073/pnas.2016553118.Peer-Reviewed Original ResearchConceptsTransplant recipient miceDNA double-strand breaksNormal B cell developmentDouble-strand breaksB cell developmentGenetic deletionB cellsLymphoid transcription factorsGlucose transporter GLUT1Gatekeeper functionGlucose uptakeRecipient miceTranscription factorsSomatic recombinationSynthetic lethalityB-cell acute lymphoblastic leukemiaCell developmentMetabolic gatekeeperRefractory B-ALLDeficient murineCell acute lymphoblastic leukemiaPoor clinical outcomeCell typesAcute lymphoblastic leukemiaGlucose transport
2017
Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL
Schjerven H, Ayongaba EF, Aghajanirefah A, McLaughlin J, Cheng D, Geng H, Boyd JR, Eggesbø LM, Lindeman I, Heath JL, Park E, Witte ON, Smale ST, Frietze S, Müschen M. Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL. Journal Of Experimental Medicine 2017, 214: 793-814. PMID: 28190001, PMCID: PMC5339667, DOI: 10.1084/jem.20160049.Peer-Reviewed Original ResearchConceptsTumor suppressor functionHuman BCR-ABL1Target genesSuppressor functionDevelopmental stage-specific expressionGenome-wide chromatinStage-specific expressionWild-type IkarosTumor suppressor geneChromatin compactionIkaros functionGene pathwaysMultiple genesExpression analysisGenetic analysisInducible expressionTumor suppressorGenetic depletionCell surface markers CD34Suppressor geneGenesIkarosBCR-ABL1Cell acute lymphoblastic leukemiaLeukemic growth
2015
STAT5 antagonism of B cell superenhancer networks initiates progenitor B cell leukemia and predicts patient survival (HEM1P.222)
Farrar M, Katerndahl C, Heltemes Harris L, Willette M, Henzler C, Yang R, Silverstein K, Frietze S, Schjerven H, Ramsey L, Hubbard G, Muschen M, Kornblau S. STAT5 antagonism of B cell superenhancer networks initiates progenitor B cell leukemia and predicts patient survival (HEM1P.222). The Journal Of Immunology 2015, 194: 50.5-50.5. DOI: 10.4049/jimmunol.194.supp.50.5.Peer-Reviewed Original ResearchB cell developmentPatient outcomesB cellsB-cell acute lymphoblastic leukemiaProgenitor B cellsCell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaCell developmentDirect clinical relevanceB-cell leukemiaShort remissionsAggressive diseasePatient survivalLymphoblastic leukemiaTranscription factor STAT5Cell leukemiaClinical relevanceTranscriptional programsLeukemiaDegree of antagonismPre-BCRSurvivalSTAT5 activationMicroarray analysisSTAT5
2014
Harnessing Negative B Cell Selection to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia
Chen Z, Shojaee S, Geng H, Lee J, Buchner M, Klemm L, Lowell C, Paietta E, Willman C, Carroll W, Melnick A, Jung J, Jumaa H, Coligan J, Bolland S, Mak T, Muschen M. Harnessing Negative B Cell Selection to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia. Blood 2014, 124: 792. DOI: 10.1182/blood.v124.21.792.792.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaTyrosine kinase inhibitorsB cell receptorInhibitory receptorsTherapeutic targetPre-BCR signalingLymphoblastic leukemiaXenograft cellsB cellsSurvival rateB-cell acute lymphoblastic leukemiaCell deathAuto-reactive clonesFree survival rateCell acute lymphoblastic leukemiaOverall survival rateWorse clinical outcomesLeukemia cellsNegative B cell selectionAdditional therapeutic targetsAvailable therapeutic interventionsG1cell cycle arrestPotent tyrosine kinase inhibitorNovel small molecule inhibitorColony formation capacityPTEN Is Essential for Normal Cytokine Signaling and Oncogenic Transformation of Pre-B Cells
Shojaee S, Cazzaniga V, Schjerven H, Buchner M, Hurtz C, Geng H, Hochhaus A, Cazzaniga G, Melnick A, Kornblau S, Graeber T, Muschen M. PTEN Is Essential for Normal Cytokine Signaling and Oncogenic Transformation of Pre-B Cells. Blood 2014, 124: 262. DOI: 10.1182/blood.v124.21.262.262.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaAlleles of PTENDeletion of PTENPI3K-Akt pathwayPI3K-Akt signalingGlucocorticoid resistanceHuman preSmall molecule inhibitorsBCR-ABL1Expression levelsMyeloid lineage leukemiasPatient-derived prePTEN deletionT-cell acute lymphoblastic leukemiaCell acute lymphoblastic leukemiaHigh expression levelsLeukemia cellsTime of diagnosisPoor clinical outcomeCell deathMature B-cell lymphomasPTEN inhibitionHuman cancersLeukemia/lymphomaB-cell lymphoma