Genetic defects in chromatin regulators in T-cell acute lymphoblastic leukemia

01 October 2013 → 30 September 2014
Funding by bilateral agreement (private and foundations)
Research disciplines
  • Natural sciences
    • Systems biology
lymphocytic leukemia
Project description

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocy1es affecting children, adolescents and adults. T-ALL is characterized by an unequal gender distribution (male-female ratio of about 3:1). In a search for X-linked tumor suppressor genes, we previously discovered loss-of-function mutations and

deletions affecting the PHF6 gene on chromosome X in T-ALL (1). In this project, we used a candidate gene approach to identify additional tumor suppressor genes on the X-chromosome that could contribute to this marked

increased risk for leukemia development in males. Notably, I discovered 5 loss-of-function mutations in the epigenetic modifier Un< (Xp11.2) in a cohort of 35 primary T-ALL patient samples (14.3%). Interestingly, the Un<

mutations were detected exclusively in male T-ALL patient samples in keeping with our hypothesis. After the identification of genetiC lesions targeting Un< in T -ALL, we performed functional in vitro and in vivo assays to

establish the tumor suppressor role of this histone demethylase in the pathogenesis of T-ALL. Part of this work was done during a 10 months period in the laboratory of Dr. H-G. Wendel (Memorial Sloan-Kettering Cancer

Center. New York, USA) and generated substantial new and exciting data, including new possibilities for therapeutic targeting of UTX mutant leukemias using recently developed ~pigenetic drugs. Given this exciting

prospect, I would like to extend my PhD work using the VLK grant in order to finalize this study. The following specific goals for this final year of my PhD thesis are: 1) further elucidate the perturbed regulatory network

resulting from UTX depletion using ChiP-sequencing of histone marks in our in vivo model systems, 2) exploring

the therapeutic effects of inhibiting H3K27 methylation or targeting specific histone modifiers in the Utx mouse tumors and 3) writing the final paper and thesis. I'm confident that given my research experience and the excellent institutional environment, I will be able to achieve these goals in a time period of one year.