Flt3-dependent transformation by inactivating c-Cbl mutations in AML.
In acute myeloid leukemia (AML), mutational activation of the receptor tyrosine kinase (RTK) Flt3 is frequently involved in leukemic transformation. However, little is known about a possible role of highly expressed wild-type Flt3 in AML. The proto-oncogene c-Cbl is an important regulator of RTK signaling, acting through its ubiquitin ligase activity and as a platform for several signaling adaptor molecules. Here, we analyzed the role of c-Cbl in Flt3 signal transduction and myeloid transformation. C-Cbl physically interacted with Flt3 and was tyrosine phosphorylated in the presence of Flt3-ligand (FL). Overexpression of a dominant-negative form of c-Cbl (Cbl-70Z) inhibited FL-induced Flt3 ubiquitylation and internalization, indicating involvement of c-Cbl in Flt3 signaling. DNA sequencing of AML bone marrow revealed a case with a c-Cbl point mutation (Cbl-R420Q). Cbl-R420Q inhibited Flt3 internalization and ubiquitylation. Coexpression of Cbl-R420Q or Cbl-70Z with Flt3 induced cytokine-independent growth and survival of 32Dcl3 cells in the absence of FL. Also, the mutant Cbl proteins altered the amplitude and duration of Flt3-dependent signaling events. Our results indicate an important role of Cbl proteins in Flt3 signal modulation. Also, the data suggest a novel mechanism of leukemic transformation in AML by mutational inactivation of negative RTK regulators.
Sargin
Bülent
B
Department of Medicine, Hematology and Oncology, and Interdisciplinary Center for Clinical Research, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48129 Münster, Germany.
Choudhary
Chunaram
C
Crosetto
Nicola
N
Schmidt
Mirko H H
MHH
Grundler
Rebekka
R
Rensinghoff
Marion
M
Thiessen
Christine
C
Tickenbrock
Lara
L
Schwäble
Joachim
J
Brandts
Christian
C
August
Benjamin
B
Koschmieder
Steffen
S
Bandi
Srinivasa Rao
SR
Duyster
Justus
J
Berdel
Wolfgang E
WE
Müller-Tidow
Carsten
C
Dikic
Ivan
I
Serve
Hubert
H
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D015973:Gene Expression Regulation, Leukemic; D005799:Genes, Dominant; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; C067419:CBL protein, human; C493849:Cbl protein, mouse