TY - JOUR
T1 - Loss of c-Cbl E3 ubiquitin ligase activity enhances the development of myeloid leukemia in FLT3-ITD mutant mice
AU - Taylor, Samuel J.
AU - Thien, Christine B.F.
AU - Dagger, Samantha A.
AU - Duyvestyn, Johanna M.
AU - Grove, Carolyn S.
AU - Lee, Benjamin H.
AU - Gilliland, D. Gary
AU - Langdon, Wallace Y.
N1 - Funding Information:
We thank Matthew Wikstrom and Geraldine Brizard for help with flow cytometry, Tracy Mann for assistance with the immunohistochemistry, Karen Waldock and Sharyn Howells from the Sir Charles Gairdner Hospital Cancer Centre for mouse irradiation, Slavica Pervan and Phil Masten for preparing histopathology sections, and Wendy Erber and Gary Hoffman for help with hematologic diagnoses. This work was supported by the National Health and Medical Research Council (project grant nos. 572516 and 634414 ), the Medical and Health Research Infrastructure Fund (Health Department of Western Australia), the L.T Thean Memorial Scholarship, and the Cancer Council Western Australia .
Publisher Copyright:
© 2015 ISEH - International Society for Experimental Hematology.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.exphem.2014.11.009
DO - 10.1016/j.exphem.2014.11.009
M3 - Article
C2 - 25534201
AN - SCOPUS:84925131621
VL - 43
SP - 191-206.e1
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 3
ER -
