气候变化领域集成服务门户(CCPortal): PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis

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DOI	10.1073/pnas.2016553118
	PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
	Pan L.; Hong C.; Chan L.N.; Xiao G.; Malvi P.; Robinson M.E.; Geng H.; Reddy S.T.; Lee J.; Khairnar V.; Cosgun K.N.; Xu L.; Kume K.; Sadras T.; Wang S.; Wajapeyee N.; Müschen M.
发表日期	2021
ISSN	00278424
卷号	118 期号:7
英文摘要	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 BCRABL1 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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	B cell leukemia \| paraoxonase 2 \| glucose transport \| lactonase
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180655
作者单位	Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, United States; Department of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fujian, 350001, China; Department of Laboratory Medicine, University of California, San Francisco, CA 94143, United States; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA 91016, United States; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 32533, United States; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, United States; Department of Immunobiology, Yale University, New Haven, CT 06511, United States
推荐引用方式 GB/T 7714	Pan L.,Hong C.,Chan L.N.,et al. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis[J],2021,118(7).
APA	Pan L..,Hong C..,Chan L.N..,Xiao G..,Malvi P..,...&Müschen M..(2021).PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis.Proceedings of the National Academy of Sciences of the United States of America,118(7).
MLA	Pan L.,et al."PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis".Proceedings of the National Academy of Sciences of the United States of America 118.7(2021).