Ikaros tumor suppressor function in leukemia

Traditional cancer treatments target all dividing cells including normal healthy cells in the body, and therefore have severe side-effects, limiting the dose tolerated by the patients. This can lead to incomplete killing of the cancer cells and subsequent relapse. New research seeks to develop new treatments that can more selectively kill the cancer cells. This requires increased understanding of how cancer cells differ from normal cells. Cancer develops when normal cells lose their control over growth and cell death. This can happen when cells are damaged in ways that lead to alterations in oncogenes (genes that promote growth) and in tumor suppressor genes (that normally limits growth). This will in turn lead to changes within the cells, as for example changes in their growth signal. In cancer, the sum of these changes has resulted in uncontrolled growth. Cancer can be defined based on what tissue or cell type it arises from (e.g. lung cancer or blood cancer). But cancer can also be defined based on the genetic changes that have occurred, and detection of these changes can be of help in diagnosis and prognosis. Furthermore, knowledge of these genetic changes can also be used to develop new targeted therapies. If we can understand what the altered gene controls, we might for instance find pharmacological medications that can inhibit growth-signals that are altered in the cancer cells. We study a gene that functions as a tumor suppressor (limits uncontrolled growth) in developing blood cells in the bone marrow. Cancer in these cells is called leukemia, and research has discovered recurrent damages in this gene (IKZF1, encoding Ikaros) in several patients with leukemia, and Ikaros is a well-established tumor suppressor in subtypes of B-cell acute lymphoblastic leukemia (B-ALL). We have uncovered unique differences between B-cell acute leukemia cells that have or do not have mutations in the IKZF1 gene. This points to unique vulnerabilities which may have the potential for being exploited by targeted therapies. We have also uncovered a new function for Ikaros in regulation of a type of white blood cells called granulocytes. These cells are a part of our innate immune defense, and genetic changes during the development of these cells in the bone marrow can lead to acute myeloid leukemia (AML). Researchers and medical doctors have found mutations in IKZF1 in AML cells from patients, which suggests a possible tumor suppressor function for Ikaros also in AML. We have now demonstrated that expression of Ikaros leads to reduced cell growth in certain AML cell lines, supporting the hypothesis that Ikaros is a tumor suppressor also in this type of acute leukemia. The project has provided new basic insight and increased our understanding for different roles of Ikaros in the development of blood cells and as tumor suppressor in acute leukemia. Such insight opens for increased understanding of the consequences of genetic mutations for diagnosis, prognosis and opens for development of new biomarkers and new targeted therapies for personalized medicine.

Tildelingen av dette forskningsprosjektet har bidratt til etablering og kompetanseøkning av et nytt forskningsmiljø innen B-celle leukemi, og styrket etableringen av samarbeid mellom klinikken og grunnforskning innen leukemi. Det muliggjorde en doktorgrad, samt rekrutering og videreutvikling av kompetanse for en Post Doc, og bidro til rekruttering av to forskerlinjestudenter fra medisinerstudiet. Prosjektet har gitt økt grunnleggende kunnskap om en transkripsjonsfaktor og tumor suppressor som er mutert i subtyper av akutt leukemi, og som er inkludert i flere kliniske gen analyser. Økt innsikt i konsekvensene av klinisk diagnostiske gen mutasjoner er et viktig steg i utviklingen av persontilpasset medisin, og kan åpne for utvikling av nye persontilpassede målrettede terapier.

Ikaros is an important transcriptional regulator of hematopoietic development and play key roles in several hematopoietic diseases, including progenitor B-cell acute lymphoblastic leukemia (pre-B ALL), cancer of mature plasma B cells (multiple myeloma, MM), common variable immunodeficiency (CVID) and autoimmunity. The overall goal of this project is to increase our understanding of the tumor suppressor function of Ikaros in leukemia. New insight obtained can open for improved diagnosis, prognosis and potential personalized targeted therapies.