PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis.
Adenosine Triphosphate
/ metabolism
Animals
Aryldialkylphosphatase
/ genetics
B-Lymphocytes
/ metabolism
Carcinogenesis
/ genetics
Cell Line, Tumor
Cells, Cultured
Glucose
/ metabolism
Glucose Transporter Type 1
/ metabolism
Humans
Membrane Proteins
/ metabolism
Mice
Mice, Inbred C57BL
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ metabolism
Protein Binding
B cell leukemia
glucose transport
lactonase
paraoxonase 2
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
16 02 2021
16 02 2021
Historique:
entrez:
3
2
2021
pubmed:
4
2
2021
medline:
23
7
2021
Statut:
ppublish
Résumé
Unlike other cell types, developing B cells undergo multiple rounds of somatic recombination and hypermutation to evolve high-affinity antibodies. Reflecting the high frequency of DNA double-strand breaks, adaptive immune protection by B cells comes with an increased risk of malignant transformation. B lymphoid transcription factors (e.g., IKZF1 and PAX5) serve as metabolic gatekeepers by limiting glucose to levels insufficient to fuel transformation. We here identified aberrant expression of the lactonase PON2 in B cell acute lymphoblastic leukemia (B-ALL) as a mechanism to bypass metabolic gatekeeper functions. Compared to normal pre-B cells, PON2 expression was elevated in patient-derived B-ALL samples and correlated with poor clinical outcomes in pediatric and adult cohorts. Genetic deletion of
Identifiants
pubmed: 33531346
pii: 2016553118
doi: 10.1073/pnas.2016553118
pmc: PMC7896313
pii:
doi:
Substances chimiques
Glucose Transporter Type 1
0
Membrane Proteins
0
SLC2A1 protein, human
0
STOM protein, human
0
Adenosine Triphosphate
8L70Q75FXE
Aryldialkylphosphatase
EC 3.1.8.1
PON2 protein, human
EC 3.1.8.1
Glucose
IY9XDZ35W2
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
Subventions
Organisme : NCI NIH HHS
ID : P01 CA233412
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA157644
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213138
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197628
Pays : United States
Organisme : Howard Hughes Medical Institute
ID : 55108547
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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