Role of TET2 in (pre)-leukemic T-ALL: TET2 to the rescue?

01 October 2019 → 30 September 2020
Funding by bilateral agreement (private and foundations)
Research disciplines
  • Medical and health sciences
    • Hematology
    • Oncology not elsewhere classified
    • Epigenetics
T-ALL stem cells DNA methylation Leukemia
Project description

T-cell acute lymphoblastic leukemia (T-ALL) is a rare but aggressive subtype of leukemia affecting the T-cell lineage. During the malignant transformation of T-cells, a clonal expansion of immature cells is selected for via the gradual accumulation of advantageous epigenetic changes and genetic mutations. Long-lived pre-leukemic stem cells (pre-LSCs) were uncovered as an initiating event in various blood- born cancers, recently also in mouse models of T-ALL. pre-LSC look phenotypically normal, but are molecularly poised to transform. They able to differentiate into functional mature blood cells but have also retained their stem cell properties, allowing clonal expansion and subsequent acquisition of extra oncogenic driver mutations, eventually leading to the onset of a full-blown leukemia. TET2, an enzyme that catalyze the DNA demethylation, has previously been shown to play pivotal roles in regulating the aberrant self-renewal of pre-LSCs. Here we will investigate the roles of TET2, and DNA demethylation, in the development of T-ALL. In addition, we will evaluate the potential of demethylating agents as a therapeutic strategy for the treatment of this aggressive leukemia