INTERFERON RESPONSIVENESS IN CML

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The family of interferon proteins are currently being applied successfully to several clinical settings (initial therapy of CML, therapy of advanced cervical cancer in combination with retinoic acid, and post-transplant maintenance therapy) alone or in combination with other biological response modifiers and chemotherapeutic agents. In CML, interferon is used in newly diagnosed patients, 26% of whom are sufficiently sensitive to interferon to develop complete cytogenetic remissions. Interferon is currently being evaluated as a means to convert major cytogenetic remissions achieved by autologous bone marrow transplants to complete cytogenetic remissions, and to suppress clonal evolution following allogeneic bone marrow transplantation. The single most limiting factor in the utility of interferons is de novo or acquired resistance to interferon. We have succeeded in isolating the 5' regulatory regions of the genes which code for the IRF-1 and IRF-2 transcriptional regulatory proteins. The IRF-1 protein may be involved in determining the level of inducibility of interferon and interferon-inducible genes, and the IRF-2 negatively regulates the interferon genes. We and others have identified additional cellular proteins which are also involved in determining the sensitivity or resistance of CML cells to alpha-interferon therapy. In addition, we identified a number of methods through which CML cells can be sensitized to alpha-interferon. We are proposing in this project to use animal models and gene transfer methods to study the functional properties of these molecules, to screen for changes in the expression or function of these molecules during the evolution of CML, and to develop the information necessary to use safety-modified viruses to introduce these molecules into CML cells for the purposes of increasing the sensitivity to alpha-interferon. For this purpose, we have developed an animal model in which genetic selection, based on Taxol chemotherapy and transduction of virally-induced marrow cells are used to promote the retention of genetically engineering hematopoietic progenitor cells. In addition, we are testing if the levels of these proteins correlate with the response to and outcome of therapy. If successful, the methods under development in this model could be applied to assays which would permit selection of patients for specific forms of therapy and to the development of novel forms of therapy for CML.