A stalled chromatin regulatory network that mediates the oncogenic activity of Meningioma-1

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Principal Investigator: KATHRIN M BERNT
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $416,556
Funding agency: National Cancer Institute

PROJECT SUMMARY
High expression of the transcriptional co-activator 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. We hypothesize that
MN1 stabilizes promoter-enhancer contacts at these sites through a BAF dependent mechanism. The goal
of this project is to uncover the molecular mechanism of MN1-mediated leukemic transformation. A better
understanding of how MN1 causes leukemia may identify opportunities for targeted therapies in a patient
population who is failing conventional AML therapy.

Terms: <AML - Acute Myeloid Leukemia><ATP phosphohydrolase><ATPase><Abscission><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Adenosine Triphosphatase><Affect><Basal Transcription Factor><Basal transcription factor genes><Behavior><Binding><Binding Sites><Blood Precursor Cell><Bone Marrow><Bone Marrow Blood-Deriving Cell><Bone Marrow Blood-Forming Cell><Bone Marrow Cells><Bone Marrow Reticuloendothelial System><Bromodomain><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancers><Cas nuclease technology><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Line><CellLine><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Chromatin><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Combining Site><Complex><Consensus Sequence><Death><Development><Diagnosis><Drug Targeting><Enhancers><Excision><Exposure to><Extirpation><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Hematopoietic><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Human><In Vitro><Individual><Kinetics><Knowledge><Malignant Neoplasms><Malignant Tumor><Mediating><Meningioma by Site><Meningioma-1><Methods><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutation><Myelogenous><Myeloid><Myeloid Progenitor><Myeloid Progenitor Cells><Myeloid Stem Cells><Nucleosomes><Oncogenic><Patients><Play><Position><Positioning Attribute><Process><Prognosis><RNA Expression><Reactive Site><Regulation><Removal><Reporting><Role><Sampling><Site><Specificity><Strains Cell Lines><Surgical Removal><System><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Variant><Variation><acute granulocytic leukemia><acute granulocytic leukemia cell><acute myeloblastic leukemia cell><acute myelocytic leukemia cell><acute myelogenous leukemia cell><acute myeloid leukemia><acute myeloid leukemia cell><acute nonlymphocytic leukemia cell><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><chromatin immunoprecipitation-sequencing><cultured cell line><developmental><drug development><gain of function><genome editing><genome mutation><genomic editing><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><in vivo><inhibitor><insight><leukemia><leukemia treatment><leukemic therapy><leukemic transformation><leukemogenesis><loss of function><malignancy><member><molecular imaging><molecule imaging><mutant><myeloid stem and progenitor cell><neoplasm/cancer><novel><overexpress><overexpression><patient population><prevent><preventing><progenitor><programs><promoter><promotor><recruit><resection><single molecule><social role><stem><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcription co-activator><transcription factor><transcriptional co-activator>