Up to 25% of children with acute lymphoblastic leukemia (ALL) will fail frontline therapy and their prognosis is dismal with only 20% cure rate. Although prognosis is better for patients with later relapses, the majority eventually succumbs to the disease (overall cure rate 40 to 50%). Usually, central nervous system (CNS) involvement, lower remission and re-induction rates and early second relapse for those who enter remission are important obstacles in the way to treatment whereas more aggressive types of therapy, including bone marrow transplantation, reached tolerability limits with toxic death rates generally ranging from 3-19%. The hypothesis of this proposal is that epigenetic drugs can be used as a targeted therapy against acute lymphoblastic leukemia, especially when classic chemotherary and/or irradiation have failed. We recently identified inactivating genetic alterations of members of the polycomb repressive complex 2 (PRC2) in T-ALL and revealed the importance of the levels of the repressive mark trimethylation of histone 3 lysine 27 (H3K27me3) in leukemogenesis. We also showed that JMJD3 is a facilitator of the oncogenic process whereas UTX is a tumor suppressor despite the fact that they execute the same enzymatic action. Using a specific chemical inhibitor we were able to kill T cell leukemia, sparing myeloid leukemia and physiological cells. In the K99 phase of this proposal (September 2014 to September 2015), we achieved substantial progress both regarding Aims 1 and 2. Especially regarding Aim 1, we 1) identified and characterized oncogene-associated super-enhancers (SE), powerful enhancer formation, important for leukemia progression that control multiple genes, 2) identified areas of high intensity of enhancer-promoter interactions, called topological domains (TD), in leukemia and 3) showed differences in TD formation in leukemia compared to physiology. Furthermore, we showed that 4) the insulator protein CTCF is an important substance of the interactions and it is needed for leukemia initiation and progression. Regarding Aim 2, we 1) identified USP7 as a partner of JMJD3 and 2) showed the important physiological roles USP7 has in leukemia growth. The existence of USP7 inhibitors with significant effects in inhibition of T cell leukemia lines (our preliminary studies) allows us to therapeutically exploit this target. We are currently generating three animals (mice) modeling mutations of UTX in human disease and are setting up models for testing of current drugs and explore metabolic pathways with the perspective to understand the connection between metabolism and epigenetics in cancer and discover new therapeutic targets in the future. We believe that these findings can be applied to other types of cancer, as the mechanisms we explore are universal. The PI has brought together experienced collaborators that will help him acquire new skills and make the transition to the independent phase. The Ntziachristos’ laboratory is well equipped and has access to state of the art equipment in Feinberg School of Medicine. This provides the PI with innovative tools to start his independent career on the crosstalk between epigenetics and metabolism in leukemia.
|Effective start/end date||9/30/15 → 8/31/18|
- National Cancer Institute (5R00CA188293-03)