Elsevier, Experimental Hematology, 3(43), p. 191-206.e1, 2015
DOI: 10.1016/j.exphem.2014.11.009
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Mutations in the 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. FLT3-ITD mutations result in a mislocalized and constitutively activated receptor, which aberrantly phosphorylates 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 hyper-activation 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.