Acute myeloid leukemia (AML) is considered a poor prognosis malignancy where patients exhibit altered glucose metabolism and stem cell signatures that contribute to AML growth and maintenance. Here, we report that the epigenetic factor, Ten-Eleven Translocation 3 (TET3) dioxygenase is overexpressed in AML patients and functionally validated human leukemic stem cells (LSCs), is required for leukemic growth by virtue of its regulation of glucose metabolism in AML cells. In human AML cells, TET3 maintains 5-hydroxymethylcytosine (5hmC) epigenetic marks and expression of early myeloid progenitor program, critical glucose metabolism and STAT5A signaling pathway genes, which also positively correlate with TET3 expression in AML patients. Consequently, TET3 depletion impedes hexokinase activity and L-Lactate production in AML cells. Conversely, overexpression of TET3 in healthy human hematopoietic stem progenitors (HSPCs) upregulates the expression of glucose metabolism, STAT5A signaling and AML associated genes, and impairs normal HSPC lineage differentiation in vitro. Finally, TET3 depletion renders AML cells highly sensitive to blockage of the TET3 downstream pathways glycolysis and STAT5 signaling via the combination of 2-Deoxy-D-glucose and STAT5 inhibitor which preferentially targets AML cells but spares healthy CD34⁺ HSPCs.

急性髓性白血病 (AML) 被认为是一种预后不良的恶性肿瘤，患者表现出葡萄糖代谢和干细胞特征的改变，这有助于 AML 的生长和维持。在这里，我们报告表观遗传因子 10-11 易位 3 (TET3) 双加氧酶在 AML 患者中过度表达，并且经过功能验证的人类白血病干细胞 (LSC) 是白血病生长所必需的，因为它调节 AML 细胞中的葡萄糖代谢. 在人类 AML 细胞中，TET3 维持 5-羟甲基胞嘧啶 (5hmC) 表观遗传标记和早期骨髓祖细胞程序、关键葡萄糖代谢和 STAT5A 信号通路基因的表达，这也与TET3呈正相关AML 患者中的表达。因此，TET3 消耗会阻碍 AML 细胞中的己糖激酶活性和 L-乳酸产生。相反，TET3 在健康人类造血干祖细胞 (HSPC) 中的过表达上调了葡萄糖代谢、STAT5A 信号传导和 AML 相关基因的表达，并在体外损害了正常的 HSPC 谱系分化。最后，TET3 耗竭使 AML 细胞对通过 2-脱氧-D-葡萄糖和 STAT5 抑制剂的组合阻断 TET3 下游通路糖酵解和 STAT5 信号传导高度敏感，该抑制剂优先靶向 AML 细胞，但不影响健康的 CD34 ⁺ HSPC。