Taylor Samuel J, Thien Christine B F, Dagger Samantha A, Duyvestyn Johanna M, Grove Carolyn S, Lee Benjamin H, Gilliland D Gary, Langdon Wallace Y
School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia; PathWest Division of Clinical Pathology, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia.
Exp Hematol. 2015 Mar;43(3):191-206.e1. doi: 10.1016/j.exphem.2014.11.009. Epub 2014 Dec 19.
Mutations in the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase (RTK) occur frequently in acute myeloid leukemia (AML), with the most common involving internal tandem duplication (ITD) within the juxtamembrane domain. Fms-like tyrosine kinase 3-ITD mutations result in a mislocalized and constitutively activated receptor, which aberrantly phosphorylates signal transducer and activator of transcription 5 (STAT5) and upregulates the expression of its target genes. c-Cbl is an E3 ubiquitin ligase that negatively regulates RTKs, including FLT3, but whether it can downregulate mislocalized FLT3-ITD remains to be resolved. To help clarify this, we combined a FLT3-ITD mutation with a loss-of-function mutation in the RING finger domain of c-Cbl that abolishes its E3 ligase activity. Mice transplanted with hematopoietic stem cells expressing both mutations rapidly develop myeloid leukemia, indicating strong cooperation between the two. Although the c-Cbl mutation was shown to cause hyperactivation of another RTK, c-Kit, it had no effect on enhancing FLT3-ITD protein levels or STAT5 activation. This indicates that c-Cbl does not downregulate FLT3-ITD and that the leukemia is driven by independent pathways involving FLT3-ITD's activation of STAT5 and mutant c-Cbl's activation of other RTKs, such as c-Kit. This study highlights the importance of c-Cbl's negative regulation of wild-type RTKs in suppressing FLT3-ITD-driven myeloid leukemia.
Fms样酪氨酸激酶3（FLT3）受体酪氨酸激酶（RTK）突变在急性髓系白血病（AML）中频繁发生，最常见的是涉及近膜结构域内的内部串联重复（ITD）。Fms样酪氨酸激酶3-ITD突变导致受体定位错误并持续激活，异常磷酸化信号转导和转录激活因子5（STAT5）并上调其靶基因的表达。c-Cbl是一种E3泛素连接酶，对包括FLT3在内的RTK起负调节作用，但它是否能下调定位错误 的FLT3-ITD仍有待解决。为了帮助阐明这一点，我们将FLT3-ITD突变与c-Cbl环指结构域中的功能丧失突变相结合，该突变消除了其E3连接酶活性。移植了表达这两种突变的造血干细胞的小鼠迅速发展为髓系白血病，表明两者之间有很强的协同作用。尽管c-Cbl突变被证明会导致另一种RTK即c-Kit的过度激活，但它对提高FLT3-ITD蛋白水平或STAT5激活没有影响。这表明c-Cbl不会下调FLT3-ITD，并且白血病是由独立的信号通路驱动的，这些通路涉及FLT3-ITD对STAT5的激活以及突变型c-Cbl对其他RTK（如c-Kit）的激活。这项研究强调了c-Cbl对野生型RTK的负调节在抑制FLT3-ITD驱动的髓系白血病中的重要性。
