2015 Hellman Fellow
PhD, Assistant Adjunct Professor, Laboratory Medicine
Project Title: Use of Mouse Models to Study the Function of Ikaros in B cell Development and Disease
All blood cells develop from blood cell-specific stem cells in the bone marrow. Blood cancer or immunological diseases can develop if these cells have loss of function or gain of function mutations in genes that control development, function, growth or survival. Ikaros is a zinc finger transcription factor that is a critical regulator of several steps in hematopoiesis, in particular in the lymphoid lineage, and has been linked to various human hematological diseases. It is well established as an important tumor suppressor in developing lymphocytes, with over 80% of BCR-ABL1+ (Ph+) pre-B ALL displaying deletions or mutations in the Ikaros gene (IKZF1). Furthermore, it was found that in other subtypes of pre-B ALL (Ph-neg), deletion or mutation of Ikaros correlated with poor prognosis. In contrast, the discovery that IMiD drug treatment of Multiple Myeloma (MM) works through degradation of Ikaros (and its close family member Aiolos) indicates that Ikaros is an obligate factor in this blood cancer of mature plasma B cells. Furthermore, recent GWAS studies have implicated both Ikaros and Aiolos as susceptibility loci for various autoimmune diseases. Thus, the link to various human diseases, together with evidence from mouse models, clearly identifies Ikaros as a critical regulator of multiple hematopoietic lineages, as well as regulating various stages within each lineage (e.g. B cell development). However, the mechanisms of how Ikaros mediates these different regulatory roles during development is poorly understood, and further basic studies of Ikaros function is required to increase our understanding of the role of Ikaros in normal development, also in order to provide a fundamental basis to understand the involvement of Ikaros in human disease.
The overall interest of Dr. Schjerven is to study transcriptional regulation of hematopoietic development and how deregulation of key transcription factors can lead to disease. The main focus of the current work is on the transcription factor Ikaros, encoded by the Ikzf1 gene. Support from the Hellman Fellows Fund allows Dr. Schjerven to pursue new directions to elucidate the mechanism by which Ikaros controls hematopoietic development and how mutations or inherited variations in this gene can lead to disease.