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Exploring downstream pathways of aberrantly activated kinases for targeted leukemia therapy

Gasser, Christelle. Exploring downstream pathways of aberrantly activated kinases for targeted leukemia therapy. 2008, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8661

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Abstract

Genetic alterations resulting in uncontrolled protein tyrosine kinases (PTKs) activity are frequently found in leukemia and in human solid cancers. Although the development of small molecule kinase inhibitors has revolutionized therapy for PTKinduced chronic myeloid leukemia, their effect is limited in cancers with several genetic alterations and increased multi-factorial drug resistance is hampering therapies. To overcome these limitations, it is indispensable to identify essential targets acting downstream of an oncogenic PTK. FLT3-ITD mediated leukemogenesis is associated with increased expression of oncogenic PIM serine/threonine kinases. To dissect their role in FLT3-ITDmediated transformation, we performed bone marrow reconstitution assays. Unexpectedly, FLT3-ITD cells deficient for PIM1 failed to reconstitute lethally irradiated recipients whereas lack of PIM2 induction did not interfere with FLT3-ITDinduced disease. PIM1-deficient bone marrow showed defects in homing and migration and displayed decreased surface CXCR4 expression and impaired CXCL12/CXCR4 signaling. Through siRNA-mediated knockdown, chemical inhibition, expression of a dominant negative mutant or and re-expression in knockout cells we found PIM1 activity to be essential for proper CXCR4 surface expression and migration of cells towards a CXCL12 gradient. PIM1 directly phosphorylated Serine 339, a residue in the CXCR4 intracellular domain essential for normal receptor recycling. In primary leukemic blasts high levels of surface CXCR4 were associated with increased PIM1 expression, and could be significantly reduced by a small molecule PIM inhibitor in some patients. Our data suggest that PIM1 activity is essential for homing and migration of hematopoietic cells through direct modification of CXCR4. Since CXCR4 is also important for homing and maintenance of cancer stem cells, PIM1 inhibitors may exert their anti-tumor effects in part by interfering with interactions with the microenvironment. We extensively tested different classes of PIM inhibitors and could show that some of these compounds could impair survival and growth of different hematopoietic cellular systems, including blasts from AML patients. The second goal of my thesis was to create a mouse model for a PTK-fusion gene, NUP214/ABL1, associated with human T-cell acute leukemia. We generated two transgenic lines expressing the NUP214/ABL1 fusion from a T-cell linked (lck) promoter. However, no phenotype was observed after more than one year. Further experiments are ongoing to analyze whether co-expression of putative collaborating oncogenes, associated in human T-cell leukemia, such as HOX11/HX11L2 is able toinduce or respectively accelerate leukemogenesis.
Advisors:Schwaller, Jürg
Committee Members:Hynes, Nancy and Cools, Jan
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Childhood Leukemia (Schwaller)
UniBasel Contributors:Schwaller, Jürg
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8661
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:110
Language:English
Identification Number:
Last Modified:22 Apr 2018 04:30
Deposited On:26 Jun 2009 08:42

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