title: Loss of c-Cbl E3 ubiquitin ligase activity enhances the development of myeloid leukemia in FLT3-ITD mutant mice.
abstract: 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.
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Taylor
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Christine B F
authors.initials: CB
authors.lastname: Thien
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Dagger
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Duyvestyn
authors.affiliation: 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.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Grove
authors.affiliation: Novartis Institute for Biomedical Research, Cambridge, MA, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia. Electronic address: wally.langdon@uwa.edu.au.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D015151:Immunoblotting; D007150:Immunohistochemistry; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D009154:Mutation; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D054829:RING Finger Domains / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C067419:CBL protein, human