Zhang Pu, Brinton Lindsey T, Gharghabi Mehdi, Sher Steven, Williams Katie, Cannon Matthew, Walker Janek S, Canfield Daniel, Beaver Larry, Cempre Casey B, Phillips Hannah, Chen Xuyong, Yan Pearlly, Lehman Amy, Scherle Peggy, Wang Min, Vaddi Kris, Baiocchi Robert, Wang Ruoning, Sampath Deepa, Alinari Lapo, Blachly James S, Lapalombella Rosa
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Sci Adv. 2022 Sep 16;8(37):eabp9005. doi: 10.1126/sciadv.abp9005.
Using a genome-wide CRISPR screen, we identified , , and as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 ()-internal tandem duplication (ITD) acute myeloid leukemia (AML) and genetically and pharmacologically validated their roles in gilteritinib sensitivity. The presence of -ITD is associated with an increase in anaerobic glycolysis, rendering leukemia cells highly sensitive to inhibition of glycolysis. Supportive of this, our data show the enrichment of single guide RNAs targeting 28 glycolysis-related genes upon gilteritinib treatment, suggesting that switching from glycolysis to oxidative phosphorylation (OXPHOS) may represent a metabolic adaption of AML in gilteritinib resistance. CDK9i/FLT3i, DHODHi/FLT3i, and PRMT5i/FLT3i pairs mechanistically converge on OXPHOS and purine biosynthesis blockade, implying that targeting the metabolic functions of these three genes and/or proteins may represent attractive strategies to sensitize AML to gilteritinib treatment. Our findings provide the basis for maximizing therapeutic impact of -ITD inhibitors and a rationale for a clinical trial of these novel combinations.
通过全基因组CRISPR筛选，我们确定了 、 和 是吉瑞替尼治疗伴有FMS样酪氨酸激酶3（ ）-内部串联重复（ITD）的急性髓系白血病（AML）时的合成致死伙伴，并从基因和药理学方面验证了它们在吉瑞替尼敏感性中的作用。 -ITD的存在与无氧糖酵解增加有关，使白血病细胞对糖酵解抑制高度敏感。与此相符的是，我们的数据显示，吉瑞替尼治疗后，靶向28个糖酵解相关基因的单向导RNA富集，这表明从糖酵解转换为氧化磷酸化（OXPHOS）可能代表了AML对吉瑞替尼耐药的一种代谢适应。CDK9i/FLT3i、DHODHi/FLT3i和PRMT5i/FLT3i组合在机制上均集中于OXPHOS和嘌呤生物合成的阻断，这意味着靶向这三个基因和/或蛋白质的代谢功能可能是使AML对吉瑞替尼治疗敏感的有吸引力的策略。我们的研究结果为最大化 -ITD抑制剂的治疗效果提供了依据，并为这些新组合的临床试验提供了理论基础。
