耶鲁大学研究人员发现克服白血病耐药性的机制

编辑翻译：菁菁

译文校对：奇奇

文献于2021年2月首次发表在最新的《美国国家科学院院刊》（Proceedings of the National Academy of Sciences）。文献发现了一种新的白血病代谢开关机制，有望帮助克服白血病耐药性。

在耶鲁大学癌症中心领导的一项新研究中，研究人员发现了一种新的白血病代谢开关机制。这种机制取决于一种名为PON2的分子。这一发现可能带来新的治疗方法。研究结果在线发表在了《美国国家科学院院刊》（PNAS）上。

骨髓抽吸物显示急性髓细胞性白血病，几处原始细胞都带有棒状小体。

B细胞是适应性免疫系统的效应细胞，标志特征是能量水平低，这可以阻止白血病的转化过程。在这项研究中，耶鲁大学的科学家确定了B细胞急性淋巴细胞性白血病（B-ALL）细胞中高表达水平的解毒内酯酶PON2是促使能量产生、推动白血病转化过程的意外机制。Stomatin是PON2的抑制剂。PON2通过从stomatin释放转运蛋白来实现葡萄糖转运蛋白1的葡萄糖摄取活性。

分子和细胞肿瘤学中心主任Markus Müschen博士，以及耶鲁癌症中心血液学研究资深学者、医学博士Athur H. 和Isabel Bunker说：“PON2对葡萄糖的摄取和能量的产生至关重要。PON2的丢失阻止了白血病的发展。在临床试验中，高水平的PON2不仅预示了白血病患者的不良预后，而且导致了更严重的疾病发作。”

研究人员指出，这项研究的发现为B细胞代谢以及B-ALL生物学提供了新见解，强调了葡萄糖和能量供应在白血病转化过程中的重要性。Muschen补充说：“从治疗的角度来看，该研究表明可以利用PON2的酶活性选择性杀死B-ALL细胞。也就是说，可以将靶向PON2作为一种新的治疗干预策略，以克服B-ALL的耐药性。”

英文原文

Researchers Discover Mechanism to Overcome Drug-Resistance in Leukemia

In a new study led by Yale Cancer Center, researchers have discovered a novel metabolic gatekeeper mechanism for leukemia. This mechanism depends on a molecule called PON2, which could lead to a new treatment for the disease. The findings were published online today in the Proceedings of the National Academy of Sciences (PNAS). 

Bone marrow aspirate showing acute myeloid leukemia. Several blasts have Auer rods. 

B cells are effector cells of the adaptive immune system and are marked by low energy levels, which prevent transformation to leukemia. In this study, Yale scientists identified high expression levels of the detoxifying lactonase PON2 in B-cell acute lymphoblastic leukemia (B-ALL) cells as an unexpected mechanism to facilitate the energy production to promote leukemic transformation. PON2 enables glucose-uptake activity of the glucose transporter 1 by releasing the transporter from its inhibitor, stomatin. 

"PON2 was critical for glucose uptake and energy production and loss of PON2 prevented leukemia development," said Markus Müschen, MD, Ph.D., Director of the Center of Molecular and Cellular Oncology and Arthur H. and Isabel Bunker Professor of Medicine (Hematology) at Yale Cancer Center and senior author of the study. "High levels of PON2 did not only predict poor outcomes of leukemia patients in clinical trials, but it also contributes to a more aggressive course of disease." 

Researchers noted findings from this study provide new insights into B-cell metabolism as well as B-ALL biology and highlights the significance of glucose and energy supply in leukemic transformation. "From a treatment perspective, the study suggests that the enzyme activity of PON2 can be leveraged to selectively kill B-ALL cells," added Müschen. "Targeting of PON2 could be developed as a novel therapeutic intervention strategy to overcome drug-resistance in B-ALL."

参考文献

Lili Pan el al., "PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis," PNAS (2021).

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