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Identification and characterization of critical downstream target genes of Signal Transducers and Activator of Transcription 5 (STAT 5) that mediate malignant transformation by tyrosine kinase fusion genes.

Applicant Schwaller Jürg
Number 100758
Funding scheme Project funding
Research institution Departement Forschung Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.10.2003 - 31.03.2007
Approved amount 220'190.00
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Keywords (2)

Molecular genetics; leukemia/lymphoma

Lay Summary (English)

Lead
Lay summary
Research of the last decade resulted in a better understanding of the genetic alterations leading to human cancer. Activating mutations in protein tyrosine kinases (PTKs) such as the BCR/ABL fusion protein play an essential role in the pathogenesis of human leukemia. The development of small molecule inhibitors targeting such oncogenic PTKs is currently revolutionizing cancer therapy. However, to overcome primary and secondary resistance mechanisms we need to identify critical downstream mediators of malignant transformation. We have previously demonstrated that a protein called signal transducers and activators of transcription 5 (STAT5) is an essential downstream mediator of malignant transformation of hematopoietic cells by various oncogenic PTKs. STAT5 binds to DNA and acts as a regulator of gene transcription controlling an expression profile that leads to cellular proliferation and survival. Our initial goal was to use a whole genome approach to identify and characterize STAT5 targets in leukemias mediated by oncogenic PTKs. After several attempts of using a whole genome approach, facing technical and logistic challenges, we decided to focus on a distinct target of STAT5: PIM kinases. PIM1 and PIM2 are members of the PIM protein serine/threonine kinases and both are expressed in hematopoietic cells. Interestingly, PIM1 and PIM2 were both found to be over-expressed in leukemic cells transformed by activation of the PTK-fusion-STAT5 signaling axe. We have demonstrated that functional interference with PIM function through dominant-negative acting mutants or by RNA-interference significantly impaired the growth and survival of leukemic cells. Interestingly, blocking PIM function did also affected cells expressing PTK-fusions carrying mutations that render them resistant against small molecule inhibitors, suggesting that blocking PIM kinase might offer a new therapeutic approach. In collaboration with S. Knapp (Oxford) we have used a structural approach to identify several rather specific small molecule inhibitors of PIM kinases. These compounds showed clear anti-leukemic activity in a panel of human leukemia cell lines as well as in a series of primary sample from acute myeloid leukemia (AML) patients, with only very limited toxicity in cord blood cells from healthy donors. Taken together, our work showed that PIM kinases, that are downstream targets of STAT5, play an important role in leukemias mediated by oncogenic PTKs. In addition, we have provided proof of principle that PIM kinases can be blocked by small molecules suggesting a new avenue for targeted leukemia therapy.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
116587 Uncovering the common key molecular mechanisms of leukemogenesis 01.04.2007 Project funding

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