From understanding the regulation of IKZF1 gene expression to the identification of pathogenic mutations in human diseases. – IKZF1GR

We have identified several enhancer and transcription factors which are important to regulate IKZF1 gene expression. We have shown that one important transcription factor is deleted in a subtype of BCP-ALL due to chromosomal rearrangement leading to low IKZF1 expression.

The transcription factor IKAROS, encoded by the IKZF1 gene, plays essential roles in the differentiation and function of B lymphocytes. Mutations and deletions of IKZF1-coding regions, which impair IKAROS expression, are found in human leukemia, immunodeficiency and autoimmunity syndromes. An adequate IKAROS expression is therefore key to its physiological function. However, how IKZF1 expression is regulated in humans is not known. We have recently identified IKZF1 deletions in patients with B cell precursor acute lymphoblastic leukemia that affect 5' non-transcribed regions, and lead to loss of IKZF1 mRNA expression from the affected allele. Non-coding regions can therefore be targets for IKZF1 mutations. We hypothesize that regulatory elements of IKZF1 are targets for pathogenic mutations. We will Investigate (1) which enhancers and transcription factors are important for IKZF1 expression in human B-cells, and (2) whether mutations of regulatory elements are found human diseases.