grant

IDP mediated transcriptional stabilization as a cause of AML

Organization CHILDREN'S HOSP OF PHILADELPHIALocation PHILADELPHIA, UNITED STATESPosted 1 Apr 2022Deadline 31 Mar 2027
NIHUS FederalResearch GrantFY2026AML - Acute Myeloid LeukemiaAcute Myeloblastic LeukemiaAcute Myelocytic LeukemiaAcute Myelogenous LeukemiaAffectAffinityAmino Acid SequenceAmino AcidsAndrogen ReceptorBasal Transcription FactorBasal transcription factor genesBindingBlood Precursor CellCancer GenesCancer-Promoting GeneCancersCell BodyCellsCessation of lifeChromatinCodeCoding SystemComplexDNA mutationDeathDiseaseDisorderDoseDrosophila Homolog of NOTCH 1EWS-FLI-1EWS-FLI1EWS-FLI1 fusion proteinEnhancersEpigeneticEpigenetic ChangeEpigenetic MechanismEpigenetic ProcessEstrogen ReceptorsEwing's Family of TumoursEwing's Sarcoma/Peripheral Primitive Neuroectodermal TumorEwing's TumorEwings sarcomaFrequenciesGene Action RegulationGene Expression RegulationGene RegulationGene Regulation ProcessGene TranscriptionGeneral Transcription Factor GeneGeneral Transcription FactorsGenesGenetic ChangeGenetic TranscriptionGenetic defectGenetic mutationHematopoieticHematopoietic Progenitor CellsHematopoietic stem cellsInnovative TherapyKineticsLeukemic CellLiquid substanceMalignantMalignant - descriptorMalignant NeoplasmsMalignant TumorMediatingMembraneMeningioma-1MiceMice MammalsMicroscopyModelingMolecular InteractionMurineMusMutationMyeloid ProgenitorMyeloid Progenitor CellsMyeloid Stem CellsNOTCH1NOTCH1 geneNephroblastomaNerve DegenerationNeuron DegenerationNuclearNucleosomesOncogenesOncogenesisOncogenicOrganellesOutcomePatientsPeptidesPhase TransitionPhysical condensationPhysiologicPhysiologicalPoly QPositionPositioning AttributePrimary Protein StructureProgenitor CellsPrognosisPropertyProteinsRNA ExpressionRenal Wilms' TumorReportingSeriesSiteStretchingStructureSystemTAN1TestingTheoretic ModelsTheoretical modelTherapeuticTranscriptionTranscription Factor Proto-OncogeneTranscription factor genesTransforming GenesTranslocation-Associated NOTCH HomologVariantVariationWilm's TumorWilms TumorWilms' Tumor of the Kidneyacute granulocytic leukemiaacute myeloid leukemiaaminoacidblood cell progenitorblood progenitorblood stem cellblood-forming stem cellcondensationepigeneticallyestrogen receptor proteinestrophileestrophilinexperimentexperimental researchexperimental studyexperimentsfluidgenome mutationhematopoietic progenitorhematopoietic stem progenitor cellhemopoietichemopoietic progenitorhemopoietic stem cellinhibitorinsightleukemialeukemia treatmentleukemic therapyliquidloss of functionmalignancymembermembrane structuremyeloid precursormyeloid stem and progenitor cellneoplasm/cancerneural degenerationneurodegenerationneurodegenerativeneurological degenerationneuronal degenerationnew approachesnew drug treatmentsnew drugsnew pharmacological therapeuticnew therapeuticsnew therapynext generation therapeuticsnotchnotch proteinnotch receptorsnovel approachesnovel drug treatmentsnovel drugsnovel pharmaco-therapeuticnovel pharmacological therapeuticnovel strategiesnovel strategynovel therapeuticsnovel therapyoverexpressoverexpressionpatient populationphysical propertypolyQpolyglutaminepreservationprogenitorprogramspromoterpromotorprotein sequencerecruitstemstem cellstargeted drug therapytargeted drug treatmentstargeted therapeutictargeted therapeutic agentstargeted therapytargeted treatmenttranscription factortumorigenesis
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Full Description

PROJECT SUMMARY
High expression of the intrinsically disordered protein Meningioma-1 (MN1) is common in AML,

and associated with a poor prognosis. Forced expression of MN1 in murine hematopoietic

progenitors induces an aggressive leukemia. We recently discovered that the primary interaction

partner of MN1 is the BAF nucleosome-positioning complex. MN1 stabilizes BAF on chromatin.

MN1 binding is associated with sustained active enhancer chromatin at enhancers regulating a

hematopoietic stem/progenitor program. Intriguingly, MN1’s entire coding frame is disordered. We

hypothesize that MN1 causes AML by overstabilizing transcriptional hubs by increasing multi-

valent, low affinity interactions that result in high local concentrations of BAF and early

hematopoietic transcription factors. A better understanding of how MN1 causes leukemia may

identify opportunities for targeted therapies in a patient population who is failing conventional AML

therapy.

Grant Number: 5R01CA269788-05
NIH Institute/Center: NIH

Principal Investigator: KATHRIN BERNT

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