Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. SHMT2 localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of SHMT2 cooperates with BCL2 in lymphoma development; loss or inhibition of SHMT2 impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support S-adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as SASH1 and PTPRM. Together, our findings reveal that amplification of SHMT2 in cooperation with BCL2 is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.

癌细胞调整其代谢活动以支持生长和增殖。然而，代谢酶活性的增加通常不被认为是恶性过程的起始事件。在这里，我们研究了酶丝氨酸羟甲基转移酶 2 (SHMT2) 在淋巴瘤起始中的可能作用。SHMT2定位于淋巴瘤中染色体 12q14.1 上拷贝数增加最频繁的区域。SHMT2的表达升高与BCL2在淋巴瘤发展中的协同作用；SHMT2的丢失或抑制会损害淋巴瘤细胞的存活。SHMT2 催化丝氨酸转化为甘氨酸并产生可用于支持S的活性单碳单元-腺苷甲硫氨酸合成。SHMT2 诱导 DNA 和组蛋白甲基化模式的变化，导致启动子沉默以前未表征的突变基因，例如SASH1和PTPRM。总之，我们的研究结果表明，SHMT2与BCL2合作的扩增足以通过表观遗传肿瘤抑制沉默启动淋巴瘤发生。