Interferon-gamma dependent tumor surveillance

Cytokines regulate a variety of important cellular functions such as survival, differentiation and proliferation within the haematopoietic system. The JAK-STAT pathway is one of the important signalling pathways downstream of cytokine receptors. Reflecting the critical role of JAK kinases and STAT transcription factors in cell growth and survival, it is not surprising that constitutive activation of Jak kinases and STAT factors has been observed in many solid and haematological malignancies. In contrast to these observations, my preliminary results show that loss of the tyrosine kinase Jak1 favours the development of B cell lymphomas induced by the Abelson oncogene. This effect may be due to a loss of IFN-g signalling, which is dependent on Jak1 and has a strong antiproliferative and apoptotic effect on pro B cells. In the current grant proposal we therefore want to investigate whether (i) loss of Jak1 favours Abelson dependent tumour progression due to the loss of an interferon-g dependent tumour surveillance pathway (ii) interferon-g dependent tumour surveillance is also relevant for other B cell malignancies, eg the B cell lymphomas observed in Em -myc mice (iii) interferon-g dependent tumour surveillance is also an important factor in the control of a T cell derived malignancy, the Tel/Jak2 induced T cell leukaemia (iv) the Jak1 downstream target STAT1 is involved in tumour surveillance Experimental strategies include in vivo and in vitro approaches. Mice that are gene disrupted for either IFN-gR, IFN-g, Jak1 or Stat1 will be infected with Abelson virus or crossed with mice strains expressing oncogenes (Em- myc and Tel/Jak2 transgenic mice). In parallel, the knockout mice will be used as source for cells deficient in single genes. These cells will be evaluated in classical in vitro transformation studies and injected into SCID mice. Cell lines derived from these studies will be subjected to detailed biochemical and molecular analysis to obtain information about loss or overexpression of particular gene products. Insights in the mechanisms of tumour surveillance and in the signalling components that favour tumour progression are not only of interest to models of tumour progression, but also highly relevant to clinical medicine. We anticipate that the findings obtained in course of this project will provide new opportunities to increase the efficacy of anti-tumour therapy.

Our project describes the effect of Interferon-gamma on lymphoid leukemia. Interferon-gamma exerts its effects via distinct signalling molecules, the tyrosine kinases Jak1 and Tyk2 and the transcription factor Stat1. Interferon gamma itself, the downstream kinases Jak1 and Tyk2 suppress the development of B lymphoid leukemia. In contrast, the transcription factor Stat1 promotes the development of B lymphoid leukemia. We delineated the reasons for this apparent contradiction and defined the effects of the Interferon-gamma signalling cascade on leukemia formation. Our results are important contributions to the field of leukemia and help to understand basic principals in tumor formation of lymphoid malignancies. Moreover, they may help to improve the treatment and diagnosis of patients suffering from lymphoid leukemia.