MLL oncoprotein levels influence leukemia lineage identities.
Myeloid-Lymphoid Leukemia Protein
/ metabolism
Humans
Leukemia, Myeloid, Acute
/ genetics
Oncogene Proteins, Fusion
/ metabolism
Cell Lineage
/ genetics
Histone-Lysine N-Methyltransferase
/ metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
Gene Expression Regulation, Leukemic
Proto-Oncogene Proteins
/ metabolism
Mutation
Translocation, Genetic
Hematopoietic Stem Cells
/ metabolism
Chromatin
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
16
02
2024
accepted:
09
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
Chromosomal translocations involving the mixed-lineage leukemia (MLL) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative MLL-rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose MLL oncoproteins promote lineage-switching events through dynamic chromatin binding at lineage-specific target genes, and may support resistance to menin inhibitors through similar changes in chromatin occupancy.
Identifiants
pubmed: 39472576
doi: 10.1038/s41467-024-53399-8
pii: 10.1038/s41467-024-53399-8
doi:
Substances chimiques
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Oncogene Proteins, Fusion
0
KMT2A protein, human
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Proto-Oncogene Proteins
0
MEN1 protein, human
0
Chromatin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9341Subventions
Organisme : Howard Hughes Medical Institute (HHMI)
ID : Henikoff
Organisme : NHGRI NIH HHS
ID : R01 HG010492
Pays : United States
Organisme : Hartwell Foundation (The Hartwell Foundation)
ID : Derek Janssens
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : NCI R35 CA297695
Organisme : American Lebanese Syrian Associated Charities (ALSAC)
ID : Mullighan
Informations de copyright
© 2024. The Author(s).
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