Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
Cancer Discov. 2021 Jun;11(6):1582-1599. doi: 10.1158/2159-8290.CD-20-0738. Epub 2021 Jan 12.
Internal tandem duplication of the FMS-like tyrosine kinase 3 gene () occurs in 30% of all acute myeloid leukemias (AML). Limited clinical efficacy of FLT3 inhibitors highlights the need for alternative therapeutic modalities in this subset of disease. Using human and murine models of FLT3-ITD-driven AML, we demonstrate that FLT3-ITD promotes serine synthesis and uptake via ATF4-dependent transcriptional regulation of genes in the serine biosynthesis pathway and neutral amino acid transport. Genetic or pharmacologic inhibition of PHGDH, the rate-limiting enzyme of serine biosynthesis, selectively inhibited proliferation of FLT3-ITD AMLs and . Moreover, pharmacologic inhibition of PHGDH sensitized FLT3-ITD AMLs to the standard-of-care chemotherapeutic cytarabine. Collectively, these data reveal novel insights into FLT3-ITD-induced metabolic reprogramming and reveal a targetable vulnerability in FLT3-ITD AML. SIGNIFICANCE: FLT3-ITD mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine biosynthesis, thereby rendering FLT3-ITD-driven leukemias dependent upon serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-ITD-driven AMLs to chemotherapy..
FMS 样酪氨酸激酶 3 基因（）内串联重复发生在所有急性髓系白血病（AML）的 30%中。FLT3 抑制剂的临床疗效有限，突出表明在这种疾病亚组中需要替代治疗方式。使用 FLT3-ITD 驱动的 AML 的人类和鼠模型，我们证明 FLT3-ITD 通过 ATF4 依赖性转录调节丝氨酸生物合成途径和中性氨基酸转运中的基因来促进丝氨酸合成和摄取。PHGDH 的遗传或药理抑制，丝氨酸生物合成的限速酶，选择性抑制 FLT3-ITD AML 的增殖和。此外，PHGDH 的药理抑制使 FLT3-ITD AML 对标准护理化疗阿糖胞苷敏感。总之，这些数据揭示了 FLT3-ITD 诱导的代谢重编程的新见解，并揭示了 FLT3-ITD AML 中可靶向的脆弱性。意义：FLT3-ITD 突变在 AML 中很常见，与预后不良有关。我们表明，FLT3-ITD 刺激丝氨酸生物合成，从而使 FLT3-ITD 驱动的白血病依赖丝氨酸进行增殖和存活。这种代谢依赖性可以通过药理学手段被利用，使 FLT3-ITD 驱动的 AML 对化疗敏感。
