T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) are aggressive hematologic malignancies that arise from malignant transformation of T-cell progenitors. T-ALL/T-LBL patients are currently treated with high-dose chemotherapy potentially followed by hematopoietic stem cell transplantation. Recently, we have shown that DNA methylation profiles of human T-ALL are uniformly perturbed as compared to normal human thymic precursor cells, suggesting that aberrant DNA methylation might serve as a uniform therapeutic target for the treatment of human T-ALL and T-LBL.
Notably, DNA hypomethylating agents, such as Azacitidine and Decitabine, have already been approved for the treatment of Acute Myleoid Leukemia (AML) and Myelodysplastic Syndrome (MDS), but only few publications have investigated the possible role of DNA hypomethylating agents for the treatment of human T-ALL and T-LBL. In this project, we want to identify the spectrum of human T-ALL and T-LBL patient samples that might respond to DNA hypomethylating agents using both diagnostics specimens, as well as tumour material obtained at relapse.
In addition, we want to investigate to what extent these DNA hypomethylating agents can be used in combination with chemotherapeutic agents that are currently used in the clinic for induction treatment of human T-ALL and T-LBL.
Finally, we want to study the putative effect of hypomethylating agents on the sensitivity of human T-ALL/T-LBL towards immunotherapy. Altogether, we believe that aberrant DNA methylation represents a vulnerable therapeutic target that should be considered for the treatment of human T-ALL and T-LBL in the near future.