Deregulation of apoptosis is one of the important features of AML and to understand the molecular mechanism underlying apoptosis and its contribution to tumor progression, this study aimed to evaluate anti-apoptotic Bcl2 protein expression in AML and correlate with FLT3 parameters for their role in prognosis of disease.Bcl2 and FLT3 protein expression was quantified by flow cytometry on leukemic blasts in total 174 de novo AML, myelodysplastic syndrome (MDS) and aplastic anemia patients.
These results support the hypothesis that Flt3-mediated signaling in AML enables accumulation of Bcl-2 and maintains a downstream block to p53 pathway apoptosis.
A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin-kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib.
+8sole patients were older (p=0.013), presented lower WBC counts (p=0.010), harbored more often ASXL1 mutations (p<0.001) and RUNX1 mutations (p=0.009), but less frequent FLT3-ITD (p=0.038), NPM1 mutations (p<0.001) and double-mutated CEBPA (p=0.038) than NK patients.
The favorable impact of NPM1 mutations on OS and EFS clearly emerged in the large group (264 [66.8%] of 395 cases) of normal-karyotype AML without FLT3-LM.
Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML.<b>Conclusions:</b> The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML.<i></i>.
Active Flt3 was linked to p85 phosphoinositide-3 (PI-3) kinase, and p85 with cbl and CrkII/CrkL by co-immunoprecipitaton assays from lysates of model cell lines and primary AML blasts.
FLT3-ITD is a mutated form of the tyrosine kinase receptor (RTK) FLT3, resulting in the constitutive activation of the kinase, occurring in about 25% of normal karyotypes' Acute Myeloid Leukemia (AML) and is linked to a bad prognosis.
Through NOD.Cg-<i>Prkdc</i><sup>scid</sup><i>Il2rg</i><sup>tmlWjl</sup>/<i>Sz</i> (NSG) xenotransplantation, we functionally identified preleukemic and leukemic stem cell populations present in FMS-like tyrosine kinase 3 internal tandem duplication-positive (<i>FLT3</i>-ITD)<sup>+</sup> AML patient samples.
The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.
Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the beta-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1).