美国冷泉港实验室Lingbo Zhang和纪念斯隆·凯特琳纪念癌症中心Chi-Chao Chen合作，发现急性髓性白血病具有维生素B6依赖性。这一研究成果发表在2020年1月13日出版的《癌细胞》上。

研究人员通过针对代谢酶的CRISPR / Cas9功能基因组筛选，发现PDXK（一种催化维生素B6生成磷酸吡哆醛（PLP）的酶）具有急性髓性白血病（AML）选择依赖性。PDX产生和AML细胞增殖均需要PDXK的激酶活性，并且在PDXK和PLP水平上对维生素B6途径进行药理阻断可产生与PDXK破坏相同的效果。PDXK破坏降低了细胞内细胞分裂所需关键代谢物的浓度。此外，PLP依赖性酶ODC1或GOT2的缺失选择性抑制了AML细胞的增殖，其下游产物可部分弥补PDXK破坏引起的增殖阻滞。该研究发现AML对维生素B6途径具有药理依赖性。

据了解，癌细胞依靠改变新陈代谢来支持其异常增殖。

附：英文原文

Title: Vitamin B6 Addiction in Acute Myeloid Leukemia

Author: Chi-Chao Chen, Bo Li, Scott E. Millman, Cynthia Chen, Xiang Li, John P. Morris, Allison Mayle, Yu-Jui Ho, Evangelia Loizou, Hui Liu, Weige Qin, Hardik Shah, Sara Violante, Justin R. Cross, Scott W. Lowe, Lingbo Zhang

Issue&Volume: 2020/01/13

Abstract: Cancer cells rely on altered metabolism to support abnormal proliferation. We performeda CRISPR/Cas9 functional genomic screen targeting metabolic enzymes and identifiedPDXK—an enzyme that produces pyridoxal phosphate (PLP) from vitamin B6—as an acutemyeloid leukemia (AML)-selective dependency. PDXK kinase activity is required forPLP production and AML cell proliferation, and pharmacological blockade of the vitaminB6 pathway at both PDXK and PLP levels recapitulated PDXK disruption effects. PDXKdisruption reduced intracellular concentrations of key metabolites needed for celldivision. Furthermore, disruption of PLP-dependent enzymes ODC1 or GOT2 selectivelyinhibited AML cell proliferation and their downstream products partially rescued PDXKdisruption induced proliferation blockage. Our work identifies the vitamin B6 pathwayas a pharmacologically actionable dependency in AML.

DOI: 10.1016/j.ccell.2019.12.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30572-0