Lili Pan, Chao Hong, Lai N Chan, Gang Xiao, Parmanand Malvi, Mark E Robinson, Huimin Geng, Srinivasa T Reddy, Jaewoong Lee, Vishal Khairnar, Kadriye Nehir Cosgun, Liang Xu, Kohei Kume, Teresa Sadras, Shaoyuan Wang, Narendra Wajapeyee, Markus Müschen
Proceedings of the National Academy of Sciences of the United States of America 2021 Feb 16Unlike 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.
Lili Pan, Chao Hong, Lai N Chan, Gang Xiao, Parmanand Malvi, Mark E Robinson, Huimin Geng, Srinivasa T Reddy, Jaewoong Lee, Vishal Khairnar, Kadriye Nehir Cosgun, Liang Xu, Kohei Kume, Teresa Sadras, Shaoyuan Wang, Narendra Wajapeyee, Markus Müschen. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2021 Feb 16;118(7)
PMID: 33531346
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