Studies on signaling pathways induced by FLT3, an important oncogene in AML

FLT3, a receptor tyrosine kinase, is expressed in hematopoietic progenitor cells. FLT3-ITD (internal tandem duplication) and D835 mutations are found in approximately 30% and 7% of Acute Myeloid Leukemia (AML) patients respectively, and correlate with a poor prognosis, thus making the mutated receptor a potential therapeutic target. FLT3 mutations cause constitutive activation of intrinsic tyrosine kinase of the receptor, leading to ligand-independent signal transduction. The aims of my studies have been to analyze the kinetics and specificity of FLT3 autophosphorylation in wild-type FLT3 and mutants, to identify novel phosphorylation sites in FLT3 receptor, to find out PTPs which can affect the signaling activity of FLT3, to investigate a novel class of tyrosine kinase inhibitors, 3, 4-diarylmaleimides for their ability to inhibit FLT3 and to determine the role of MEK5/ERK5 signaling in FLT3-ITD mediated transformation. Using phosphospecific antibodies, we have identified 3 novel phosphorylation sites in FLT3, Y726, Y793 and Y842, and studied their kinetics and specificity. The additional eight phosphorylated tyrosine residues in FLT3 were shown to have different phosphorylation characteristics in the wild-type FLT3 compared to the mutated receptors. We have found that the protein tyrosine phosphatase DEP-1 serves as a negative regulator of FLT3 activation and signaling. Furthermore, 3,4-diarylmaleimides inhibitors have been found to be able to inhibit FLT3-ITD in both transfected cells as well as primary ITD-positive AML blasts leading to induction of apoptosis in those cells. These inhibitors also reduced the phosphorylation of signaling molecules downstream of FLT3-ITD such as ERK and STAT5. The last paper in the thesis revealed the anti-apoptotic effect of MEK5/ERK5 on FLT3-ITD expressing leukemia cells.

Grantor dc:publisher

Department of Laboratory Medicine, Lund University

Year dc:date

2011

Author dc:creator

• Razumovskaya, Elena

• Medicinal Chemistry
• FLT3
• AML
• RTK
• oncogene
• ERK5
• hematopoiesis

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

urn:isbn:978-91-86871-59-8

OAI identifier oai:identifier

oai:lup.lub.lu.se:b75c7eae-beb2-49e4-a14a-4d8f16b4d5fb