FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome.
Journal
Blood cancer journal
ISSN: 2044-5385
Titre abrégé: Blood Cancer J
Pays: United States
ID NLM: 101568469
Informations de publication
Date de publication:
06 10 2020
06 10 2020
Historique:
received:
05
06
2020
accepted:
18
09
2020
revised:
15
09
2020
entrez:
7
10
2020
pubmed:
8
10
2020
medline:
7
5
2021
Statut:
epublish
Résumé
Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.
Identifiants
pubmed: 33024076
doi: 10.1038/s41408-020-00362-7
pii: 10.1038/s41408-020-00362-7
pmc: PMC7538974
doi:
Substances chimiques
F-Box Proteins
0
Tumor Suppressor Proteins
0
FBXO11 protein, human
EC 2.1.1.319
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
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
98Subventions
Organisme : NCI NIH HHS
ID : R01 CA237039
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135787
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027015
Pays : United States
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