Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 06 2022
01 06 2022
Historique:
received:
14
04
2021
accepted:
10
05
2022
entrez:
1
6
2022
pubmed:
2
6
2022
medline:
7
6
2022
Statut:
epublish
Résumé
Acute B-cell lymphoblastic leukemia (B-ALL) results from oligo-clonal evolution of B-cell progenitors endowed with initiating and propagating leukemia properties. The activation of both the Rac guanine nucleotide exchange factor (Rac GEF) Vav3 and Rac GTPases is required for leukemogenesis mediated by the oncogenic fusion protein BCR-ABL. Vav3 expression becomes predominantly nuclear upon expression of BCR-ABL signature. In the nucleus, Vav3 interacts with BCR-ABL, Rac, and the polycomb repression complex (PRC) proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for the proliferation, Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, mono-ubiquitination of H2A(K119) (H2AK119Ub) and repression of PRC-1 (PRC1) downstream target loci, of leukemic B-cell progenitors. Vav3 deficiency results in de-repression of negative regulators of cell proliferation and repression of oncogenic transcriptional factors. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.
Identifiants
pubmed: 35650206
doi: 10.1038/s41467-022-30651-7
pii: 10.1038/s41467-022-30651-7
pmc: PMC9160250
doi:
Substances chimiques
Proto-Oncogene Proteins c-vav
0
VAV3 protein, human
0
Polycomb Repressive Complex 1
EC 2.3.2.27
Fusion Proteins, bcr-abl
EC 2.7.10.2
PHLPP2 protein, human
EC 3.1.3.16
Phosphoprotein Phosphatases
EC 3.1.3.16
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3056Subventions
Organisme : NCI NIH HHS
ID : R50 CA211404
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237016
Pays : United States
Organisme : NHGRI NIH HHS
ID : R41 HG011219
Pays : United States
Organisme : NHGRI NIH HHS
ID : R42 HG011219
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK126108
Pays : United States
Informations de copyright
© 2022. The Author(s).
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