PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
Menée in vitro et à l'aide de modèles murins modifiés génétiquement, cette étude met en évidence un mécanisme par lequel la paraoxonase PON2, en interagissant avec un inhibiteur du transport de glucose, favorise la leucémogenèse
B lymphoid transcription factors (e.g., IKZF1 and PAX5) not only mediate B cell lineage commitment but also repress glucose transport and energy supply, thus acting as metabolic gatekeepers. While previous studies showed regulation of metabolic gatekeeper functions at the transcriptional level, we here discovered a mechanism of regulation based on protein–protein interactions between PON2 and the glucose-transport inhibitor stomatin (STOM).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.The GEO accession number for the gene expression profile from ECOG E2993 (191 B-cell acute lymphoblastic leukemia, B-ALL, and normal samples) is GSE34861. The GEO accession number for RNAseq data for immunocyte populations representing all lineages and several differentiation stages is GSE109125. Additional accession numbers for gene expression data used in this study include: GSE13159 (2096 blood or bone marrow samples of acute and chronic leukemia patients), GSE11877 (COG P9906, 207 B-ALL), GSE5314 (ECOG E2993, 54 ALL), GSE28460 (COG P9906, 29 paired B-ALL samples), GSE10846 (diffuse large B cell lymphoma, DLBCL), GSE22762 (chronic lymphocytic leukemia, CLL), and GSE9782 (multiple myeloma, MM). Gene expression data for follicular cell lymphoma were obtained from the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). Gene expression data from 132 pediatric ALL patient samples were obtained from: http://www.stjuderesearch.org/data/ALL3. All additional data are included in the article and SI Appendix. Further information requests and requests for reagents should be directed to and will be fulfilled by lead contact, M.M. (markus.muschen{at}yale.edu).