Suknuntha Kran, Choi Yoon Jung, Jung Ho Sun, Majumder Aditi, Shah Sujal, Slukvin Igor, Ranheim Erik A
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, United States.
Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, United States.
Front Oncol. 2020 Dec 9;10:585151. doi: 10.3389/fonc.2020.585151. eCollection 2020.
Numerous recurrent genetic mutations are known to occur in acute myeloid leukemia (AML). Among these common mutations, Fms-like tyrosine kinase 3 remains as one of the most frequently mutated genes in AML. We observed apparent marrow expansion of megakaryocytes in three out of six patients with Flt3-mutated AML following treatment with a recently FDA-approved Flt3 inhibitor, gilteritinib which possesses activity against internal tandem duplication and tyrosine kinase domain Flt3 mutations and also inhibits tyrosine kinase AXL. To assess whether biopsy findings can be attributed to promotion of megakaryocytic (Mk) differentiation with gilteritinib, we devised a cellular assay by overexpressing double mutated Flt3-ITD in chronic myeloid leukemia cell line K562 to study Mk differentiation in the presence of Flt3 and AXL inhibitors with non-mutually exclusive mechanisms. These experiments demonstrated the lack of direct effect Flt3 inhibitors gilteritinib and quizartinib on megakaryocytic differentiation at either transcriptional or phenotypic levels, and highlighted antileukemic effects of AXL receptor tyrosine kinase inhibitor and its potential role in megakaryocytic development.
已知急性髓系白血病（AML）中会出现许多复发性基因突变。在这些常见突变中，Fms样酪氨酸激酶3仍然是AML中最常发生突变的基因之一。我们观察到，在最近获得美国食品药品监督管理局（FDA）批准的Flt3抑制剂吉列替尼治疗后，6例Flt3突变型AML患者中有3例出现明显的巨核细胞骨髓扩张。吉列替尼具有抗内部串联重复和酪氨酸激酶结构域Flt3突变的活性，还能抑制酪氨酸激酶AXL。为了评估活检结果是否可归因于吉列替尼促进巨核细胞（Mk）分化，我们通过在慢性髓系白血病细胞系K562中过表达双突变Flt3-ITD设计了一种细胞试验，以研究在存在具有非互斥机制的Flt3和AXL抑制剂的情况下Mk的分化。这些实验表明，Flt3抑制剂吉列替尼和奎扎替尼在转录或表型水平上对巨核细胞分化均无直接影响，并突出了AXL受体酪氨酸激酶抑制剂的抗白血病作用及其在巨核细胞发育中的潜在作用。
