CBL Exon 8/9 Mutants Activate the FLT3 Pathway and Cluster in Core Binding Factor/11q Deletion Acute Myeloid Leukemia/Myelodysplastic Syndrome Subtypes

• DOI: 10.1158/1078-0432.ccr-08-1325
• Publication Date: 2009-03-11T02:13:48Z
• Authors: Carola Reindl; Hilmar Quentmeier; Konstantin Petrop...; Philipp A. Greif; Tobias Benthaus; Bob Argiropoulos; Gudrun Mellert; Sridhar Vempati; Justus Duyster; Christian Buske; Stefan K. Bohlander; Keith R. Humphries; Wolfgang Hiddemann; Karsten Spiekermann
• Keywords: Core binding factor; Midostaurin

CBL is a negative regulator of activated receptor tyrosine kinases (RTK). In this study, we determined the frequency mutations in acute leukemias and evaluated oncogenic potential mutant CBL.The cDNA 300 myeloid leukemia (AML)/myelodysplastic syndrome (MDS) lymphoblastic (ALL) patients 82 human leukemic cell lines was screened for aberrations linker RING finger domain CBL. The identified mutants hematopoietic cells.We 3 279 AML/MDS expressing exon 8/9 deletion mutants. Three four cases at diagnosis expressed deleted transcripts missing 8 or 8/9. remission samples weak no expression detected. No were found normal tissues. One 116 sequenced carried R420G missense mutation. All with belonged to core binding factor 11q AML subtypes. Functionally, negatively regulated FMS-like kinase (FLT3) activity interacted FLT3 via autophosphorylation sites Y589 Y599 colocalized vivo. Expression CBLDeltaexon8 CBLDeltaexon8+9 FLT3-WT-Ba/F3 cells induced growth factor-independent proliferation associated downstream targets signal transducer activator transcription 5 (STAT5) protein B (AKT). ligand-dependent hyperproliferation could be abrogated by treatment PTK inhibitor PKC412 (midostaurin).CBL exon8/9 occur genetically defined subtypes transform constitutively activating pathway. This phenotype resembles one mutated RTKs suggests that might benefit from inhibitors.