PuSH - Publication Server of Helmholtz Zentrum München

Polzer, H. ; Janke, H. ; Schmid, D. ; Hiddemann, W. ; Spiekermann, K.

Casitas B-lineage lymphoma mutants activate AKT to induce transformation in cooperation with class III receptor tyrosine kinases.

Exp. Hematol. 41, 271-280 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
In addition to overexpression and the occurrence of activating mutations, receptors can be aberrantly activated by impaired downregulation. In this study, we show that an oncogenic mutant of the ubiquitin ligase casitas B-lineage lymphoma (CBL; CBLΔexon8), which is found in acute myeloid leukemia patients, predominantly cooperates with receptor tyrosine kinase (RTK) class III receptors (PDGFRA, PDGFRB, KIT, and FLT3), but not with non-class III RTKs or cytokine receptors, to induce IL-3-independent growth of Ba/F3 cells. In cells coexpressing RTK class III/CBLΔexon8, receptor internalization was delayed, and cells were protected from apoptosis after cytokine withdrawal. Ligand-stimulated Ba/F3 cells and acute myeloid leukemia cell lines coexpressing the CBL deletion mutant and FLT3 showed enhanced AKT phosphorylation. Combined pharmacologic inhibition of the PI3K/AKT pathway and FLT3 had an additive effect on cell proliferation. The transforming potential of the CBL mutant was completely abolished by the mutation of the CBL PTB domain and was decreased by the mutation of tyrosines 589 and 591 in the juxtamembrane domain of FLT3. A constitutively active AKT1 mutant (E17K) recapitulated the phenotype induced by the CBL deletion mutant in Ba/F3 cells. This study reveals FLT3-CBL interaction sites and the AKT pathway as critical mediators of transformation by oncogenic CBL mutants.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0301-472X
e-ISSN 0301-472X
Journal Experimental Hematology
Quellenangaben Volume: 41, Issue: 3, Pages: 271-280 Article Number: , Supplement: ,
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)