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http://purl.uniprot.org/citations/33531346http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/33531346http://www.w3.org/2000/01/rdf-schema#comment"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 Pon2 had no measurable impact on normal B cell development. However, in mouse models for BCR-ABL1 and NRASG12D-driven B-ALL, deletion of Pon2 compromised proliferation, colony formation, and leukemia initiation in transplant recipient mice. Compromised leukemogenesis resulted from defective glucose uptake and adenosine triphosphate (ATP) production in PON2-deficient murine and human B-ALL cells. Mechanistically, PON2 enabled glucose uptake by releasing the glucose-transporter GLUT1 from its inhibitor stomatin (STOM) and genetic deletion of STOM largely rescued PON2 deficiency. While not required for glucose transport, the PON2 lactonase moiety hydrolyzes the lactone-prodrug 3OC12 to form a cytotoxic intermediate. Mirroring PON2 expression levels in B-ALL, 3OC12 selectively killed patient-derived B-ALL cells but was well tolerated in transplant recipient mice. Hence, while B-ALL cells critically depend on aberrant PON2 expression to evade metabolic gatekeeper functions, PON2 lactonase activity can be leveraged as synthetic lethality to overcome drug resistance in refractory B-ALL."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.org/dc/terms/identifier"doi:10.1073/pnas.2016553118"xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Lee J."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Pan L."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Xu L."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Wang S."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Hong C."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Xiao G."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Chan L.N."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Geng H."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Muschen M."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Kume K."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Wajapeyee N."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Reddy S.T."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Robinson M.E."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Malvi P."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Sadras T."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Khairnar V."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/author"Cosgun K.N."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/date"2021"xsd:gYear
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/name"Proc Natl Acad Sci U S A"xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/pages"e2016553118"xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/title"PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis."xsd:string
http://purl.uniprot.org/citations/33531346http://purl.uniprot.org/core/volume"118"xsd:string
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