0000000000876634
AUTHOR
Marie-christine Blum
Analysis of Differentially Activated Signaling Pathways in Myeloproliferative Disease Using Kinomics Chip Profiling
Abstract In a multitude of cases, oncogenic mutations are gain of function mutations that confer a constitutively activated gene product. Currently, evidence from a large body of experimental studies suggests that oncogenic transformation induced by activating kinase mutations is not sufficiently explained by constitutive kinase activation alone but is a result of aberrantly activated signaling pathways in affected cells. The JAK2V617F-mutation is a highly prevalent molecular marker in Ph-negative myeloproliferative disease (MPD). In vitro, Ba/F3-cells expressing both erythropoietin receptor (EpoR) and the JAK2V617F-mutation show constitutive activation of the JAK-STAT pathway and cytokine …
Different FLT3-ITD Integration Sites Are Associated with Differential Sensitivity to Tyrosine Kinase Inhibitors (TKI) In Vitro.
Abstract Abstract 1709 Introduction: Currently, small molecule FLT3 tyrosine kinase inhibitors (TKIs) are promising therapeutic approaches to overcome the dismal prognosis of AML patients harbouring FLT3-ITD mutations. However, up to 30% of these patients show primary resistance to FLT3-TKIs. Recently, we uncovered a novel mechanism of primary resistance to FLT3 TKIs in a patient displaying an atypical integration site of ITD within the beta2-sheet (ITD_A627E). The data suggested that atypical integration sites of ITDs within the tyrosine kinase domain-1 (TKD1) of FLT3 (beta1-sheet, nucleotide binding loop and beta2-sheet) are associated with rewired signaling and differential responsivenes…