Department of Medicine, Northwestern University, Chicago, Illinois, USA.
Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.
J Biol Chem. 2020 Jul 10;295(28):9663-9675. doi: 10.1074/jbc.RA120.013206. Epub 2020 May 28.
Acute myeloid leukemia (AML) with mixed lineage leukemia 1 () gene rearrangement is characterized by increased expression of a set of homeodomain transcription factors, including homeobox A9 (HOXA9) and HOXA10. The target genes for these regulators include fibroblast growth factor 2 () and Ariadne RBR E3 ubiquitin ligase 2 (). FGF2 induces leukemia stem cell expansion in MLL1-rearranged AML. ARIH2 encodes TRIAD1, an E3 ubiquitin ligase required for termination of emergency granulopoiesis and leukemia suppressor function in -rearranged AML. Receptor tyrosine kinases (RTKs), including the FGF receptor, are TRIAD1 substrates that are possibly relevant to these activities. Using transcriptome analysis, we found increased activity of innate immune response pathways and RTK signaling in bone marrow progenitors from mice with -rearranged AML. We hypothesized that sustained RTK signaling, because of decreased TRIAD1 activity, impairs termination of emergency granulopoiesis during the innate immune response and contributes to leukemogenesis in this AML subtype. Consistent with this, we found aberrantly sustained emergency granulopoiesis in a murine model of -rearranged AML, associated with accelerated leukemogenesis. Treating these mice with an inhibitor of TRIAD1-substrate RTKs terminated emergency granulopoiesis, delayed leukemogenesis during emergency granulopoiesis, and normalized innate immune responses when combined with chemotherapy. Emergency granulopoiesis also hastened postchemotherapy relapse in mice with -rearranged AML, but remission was sustained by ongoing RTK inhibition. Our findings suggest that the physiological stress of infectious challenges may drive AML progression in molecularly defined subsets and identify RTK inhibition as a potential therapeutic approach to counteract this process.
急性髓系白血病（AML）伴混合谱系白血病 1 () 基因重排的特征是一组同源盒转录因子的表达增加，包括同源盒 A9（HOXA9）和 HOXA10。这些调节剂的靶基因包括成纤维细胞生长因子 2（）和 Ariadne RBR E3 泛素连接酶 2（）。FGF2 诱导 MLL1 重排 AML 中的白血病干细胞扩增。ARIH2 编码 TRIAD1，它是 E3 泛素连接酶，是 - 重排 AML 中紧急粒细胞生成终止和白血病抑制功能所必需的。受体酪氨酸激酶（RTKs），包括 FGF 受体，是 TRIAD1 的底物，可能与这些活性相关。使用转录组分析，我们发现 - 重排 AML 小鼠骨髓祖细胞中固有免疫反应途径和 RTK 信号的活性增加。我们假设，由于 TRIAD1 活性降低，持续的 RTK 信号会损害紧急粒细胞生成的终止，从而导致这种 AML 亚型的白血病发生。与这一假设一致的是，我们在 - 重排 AML 的小鼠模型中发现了异常持续的紧急粒细胞生成，与加速的白血病发生相关。用 TRIAD1-底物 RTK 的抑制剂治疗这些小鼠可终止紧急粒细胞生成，在紧急粒细胞生成期间延迟白血病发生，并在与化疗联合使用时使固有免疫反应正常化。紧急粒细胞生成也加速了 - 重排 AML 小鼠的化疗后复发，但持续的 RTK 抑制可维持缓解。我们的研究结果表明，感染挑战的生理应激可能会推动特定分子定义的 AML 进展，并确定 RTK 抑制作为一种潜在的治疗方法来对抗这一过程。
