B9: Causes and consequences of the epigenetic disturbances in T-prolymphocytic leukemia

T-cell prolymphocytic leukemia (T-PLL) is an aggressive post-thymic T-cell malignancy characterized by the recurrent inv(14)/t(14;14) or t(X;14) leading to activation of TCL1 or MTCP1, respectively. T-PLL shares with B-CLL several morphologic features, the mature lymphocyte phenotype, the pathogenetic importance of TCL1 activation and ATM inactivation, and a mutational landscape dominated by recurrent chromosomal imbalances rather than recurrently mutated genes. We previously observed that T-PLLs show a unique DNA methylation phenotype among hematologic malignancies characterized by massive hypomethylation, which is not recapitulated in TCL1A-activated B-CLL. Firstly, we thus aim at investigating the role of TCL1A protein in inducing epigenetic alterations through various comparative epigenomic analyses in different models and contexts. To this end, we will perform comparisons of primary B- and T-cell tumors in humans, TCL1A-transgenic mice and respective in vitro models. Secondly, we want to decipher the role of tissue, maturation and/or transformation-associated co-factors to be determined or already identified in our integrated OMICs analyses in shaping the epigenome of T PLL cells, and thirdly, will complement our investigations by examining the potential role of non-coding RNAs in mediating the epigenetic enhancer switching in T PLL.

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