Integration of the expanded genomic landscape of T-PLL with epigenetic profiles, TCR signaling competence, and drug sensitivity.

• Applicant: Dr. Marco Herling, since 12/2020
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433072295

T-cell prolymphocytic leukemia (T-PLL) is the most common leukemic mature T-cell lymphoma in adults. It is an overall rare (0.6 / million), poor prognostic, yet understudied tumor. T-PLL´s molecular hallmark and suspected initiating event is the constitutive transcriptional activation of the T-cell leukemia 1 (TCL1) oncogene based on a genomic inversion / translocation of chromosome 14 or its homologue Mature T cell Proliferation 1 (MTCP1) based on a translocation t(X;14). Despite TCL1´s central role in T-PLL´s pathophysiology, the mechanisms underlying the respective genomic alterations as well as TCL1s effector functions are so far not resolved. T-PLL´s chemotherapy resistance translates into an average patient survival of <20 months. There are no approved drugs for T-PLL and numerous exploratory trials to test novel options are not feasible. Aiming at the development of novel treatment strategies, first inhibitor screens uncovered promising, but also differential sensitivities. We are still far from informed implementation of new molecular knowledge into clinical application. This is mostly due to a lack of integration of available multi-level profiling data and a rudimentary understanding of their functional impact. Moreover, gene-regulatory, particularly epigenetic changes and metabolic cellular states, both also known to influence treatment responses, have not been addressed in T-PLL.Thus, we aim at establishing a comprehensive molecular map of T-PLL by integrating genomic, epigenetic, and phenotypic data (Aim 1). Using these defined molecular maps, we will (Aim 2) answer basic questions regarding the molecular mechanisms of T-PLL biology (Ulm). For that, we will describe breakpoint regions of TCL1 and MTCP1 genomic loci in order to elucidate mechanism of early T-PLL development. In addition, we will investigate the breakpoints of common secondary alterations in T-PLL. Overall, we will establish a model of deregulated networks and their underlying mechanisms by integrating genomic architecture with epigenetic and transcriptional patterns. This will enable a better basal understanding of T-PLL’s pathogenesis. Furthermore, we will (Aim 3) follow a translational approach to identify predictors of treatment responses towards available targeted compounds (Cologne). In conjunction with clinical information, we will use defined molecular alterations (including those identified in Aim 1 and Aim 2) to predict differential compound sensitivities, and to support individual treatment decisions and future trial designs. With this proposal, we apply for funding to finance additional sequencing studies. Respective complementary and subsequent work of (major parts of Aim 2 and Aim 3) is funded by the DFG and the EU / BMBF. Eventually, by developing a concept of how drug activity patterns relate to T-PLL’s molecular landscape, we will eventually identify biomarkers that discern T-PLL patient subsets based on vulnerabilities towards targeted compounds.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Reiner Siebert; Dr. Rabea Wagener
• Ehemalige Antragstellerin: Dr. Alexandra Schrader, until 12/2020