Therapeutic Modulation of Oncogenic Histone Demethylases in T cell Leukemia and Lymphoma

Project: Research project

Project Details

Description

Background and supporting rationale: Although the cure rate for T Cell Acute Lymphoblastic Leukemia (T-ALL), a frequent pediatric leukemia, has been improved dramatically during the last couple of decades, the overall prognosis remains dismal due to frequent disease relapse and the absence of non-cytotoxic targeted therapy options. Despite the fact that drugs targeting the function of epigenetic inhibitors have been approved in the context of other hematopoietic malignancies, such drugs are currently not available for T-ALL treatment. This is mainly due to the lack of understanding of the exact mechanisms of action of specific chromatin modulators in T-ALL, although some light was shed recently mainly through the identification of mutations of specific enzymes with chromatin-related action in T cell leukemia. We hypothesize here that epigenetic drugs can be used as a targeted therapy against leukemia especially in cases where more generalized genotoxic treatments have failed. Using mouse models and primary human samples, we recently identified inactivating genetic alterations of members of the polycomb repressive complex 2 (PRC2) and revealed the importance of the levels of the repressive mark H3K27me3 in leukemogenesis. In this application we hypothesize that regulation of H3K27me by specific demethylases is key for the induction and progression of T-ALL and that targeting of such enzymes could lead to disease remission. We will address this hypothesis in the following experimental aims:
Aim 1. Characterizing a H3K27me3-associated prognostic signature in pediatric T- ALL. This Aim will dissect the genetic status of EZH2, JMJD3 and UTX and their associated epigenetic and transcriptional changes in a plethora of diagnosis and relapse samples across the spectrum pediatric T-ALL.
Aim 2. Testing a small molecule inhibitor against JMJD3 demethylase on primary cells and human:mouse xenograft models of T-LL. We will directly test the ability of novel small molecule inhibitors targeting JMJD3 in human xenografts using representative primary cells with combinations of EZH2 and UTX mutations.
Aim 3. Dissecting the molecular mechanisms of action of the JMJD3 inhibitor GSKJ4 in T-LL. Our hypothesis is that the GSK inhibitor inactivates JMJD3 function leading to H3K27 hyper-methylation (and silencing) of key oncogenic pathways.
StatusFinished
Effective start/end date10/1/159/30/16

Funding

  • American Society of Hematology (AGMT-11/3/15)

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