PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
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PON2 破坏 B 细胞中的代谢看门人功能，促进白血病发生
DOI：
10.1073/pnas.2016553118
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发表时间：
2021-02
期刊：
影响因子：
--
通讯作者：
Muschen Markus
中科院分区：
文献类型：
--
作者：
Pan Lili;Hong Chao;Chan Lai N.;Xiao Gang;Malvi Parman;Robinson Mark E.;Geng Huimin;Reddy Srinivasa T.;Lee Jaewoong;Khairnar Vishal;Cosgun Kadriye Nehir;Xu Liang;Kume Kohei;Sadras Teresa;Wang Shaoyuan;Wajapeyee Narendra;Muschen Markus
显著性B淋巴转录因子（例如，IKZF 1和PAX 5）不仅介导B细胞谱系定型，而且抑制葡萄糖转运和能量供应，因此充当代谢看门人。虽然之前的研究表明代谢看门人功能在转录水平上进行调节，但我们在这里发现了一种基于PON 2和葡萄糖转运抑制剂气孔蛋白（STOM）之间蛋白质-蛋白质相互作用的调节机制。与其他细胞类型不同，发育中的B细胞经历多轮体细胞重组和超突变以进化出高亲和力抗体。由于DNA双链断裂的频率很高，B细胞的适应性免疫保护伴随着恶性转化风险的增加。B淋巴转录因子（例如，IKZF 1和PAX 5）通过将葡萄糖限制在不足以促进转化的水平而充当代谢守门人。我们在此鉴定了内酯酶PON 2在B细胞急性淋巴细胞白血病（B-ALL）中的异常表达作为绕过代谢看门人功能的机制。与正常前B细胞相比，患者来源的B-ALL样本中PON 2表达升高，并且与儿科和成人队列中的不良临床结局相关。Pon 2基因缺失对正常B细胞发育没有可测量的影响。然而，在BCR-ABL 1和NRASG 12 D驱动的B-ALL小鼠模型中，Pon 2的缺失损害了移植受体小鼠的增殖、集落形成和白血病起始。在PON 2缺陷的小鼠和人B-ALL细胞中，葡萄糖摄取和三磷酸腺苷（ATP）产生缺陷导致白血病发生受损。从机制上讲，PON 2通过从其抑制剂气孔蛋白（STOM）释放葡萄糖转运蛋白GLUT 1来实现葡萄糖摄取，STOM的遗传缺失在很大程度上挽救了PON 2缺乏症。虽然不需要葡萄糖转运，但P0 N 2内酯酶部分水解内酯-前药30 C12以形成细胞毒性中间体。在B-ALL中，3 OC 12的镜像PON 2表达水平选择性地杀死患者来源的B-ALL细胞，但在移植受体小鼠中耐受良好。因此，虽然B-ALL细胞严重依赖于异常的PON 2表达来逃避代谢看门人功能，但PON 2内酯酶活性可以作为合成致死性来克服难治性B-ALL中的耐药性。
Significance 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.
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B细胞身份是针对恶性转化的代谢障碍。
影响因子：
2.6
作者：
Chan LN;Müschen M
通讯作者：
Müschen M
影响因子：
28.2
作者：
Parmenter TJ;Kleinschmidt M;Kinross KM;Bond ST;Li J;Kaadige MR;Rao A;Sheppard KE;Hugo W;Pupo GM;Pearson RB;McGee SL;Long GV;Scolyer RA;Rizos H;Lo RS;Cullinane C;Ayer DE;Ribas A;Johnstone RW;Hicks RJ;McArthur GA
通讯作者：
McArthur GA
影响因子：
2.3
作者：
Jiang-guo Zhang;Fengyun Gong;Ling Li;Manzhi Zhao;Jianxin Song
通讯作者：
Jiang-guo Zhang;Fengyun Gong;Ling Li;Manzhi Zhao;Jianxin Song
影响因子：
20.3
作者：
Harvey, Richard C.;Mullighan, Charles G.;Willman, Cheryl L.
通讯作者：
Willman, Cheryl L.
影响因子：
100.3
作者：
Muschen, Markus
通讯作者：
Muschen, Markus