Marco Herling / Elena Vasyutina - A 5

Context-specific mechanisms of the TCL1 oncogene in T- and B-cell leukemias

Abstract

This application aims to better establish how key cellular pathways of B- and T-cell tumors are modulated by the non-conventional TCL1 oncogene. Aberrantly high TCL1 levels are a hallmark of the lymphatic neoplasms of CLL and T-PLL, with highest levels signifying poorer clinical outcomes. TCL1 transgenic (tg) mice closely resemble human leukemogenesis. Nevertheless, the molecular concept around the non-kinase protein TCL1 is incomplete. We established TCL1 as an integral part of activation-induced AKT kinase complexes. Our mass spectrometry (MS) screens identified a spectrum of TCL1 targets involved in such functional categories as DNA damage response (DDR) and mitotic checkpoint control (MCC).
We propose here an integrative model of pleiotropic TCL1 acting on several distinct, but interlinked, molecular axes towards leukemogenesis. In Aim I, we discern the molecular impacts of TCL1 on its primary targets in defined lymphocyte relevant contexts (B vs T) upon defined stimuli of antigen receptor engagement, induced DDR, or mitotic activity by using quantitative MS. Work packages will further study the molecular and cell phenotypic consequences of TCL1’s engagement on DDR or MCC, including the definition of involved interacting domains and downstream target activation. Besides TCL1-transfected cell lines and primary human samples, we employ mouse models that will address the leukemic stage dependence of TCL1-mediated alterations.

Clinical/medical relevance and sustainability in disease understanding

TCL1 is causally implicated in the pathogenesis of multiple B- and T-cell leukemias. There is a high need to provide an integrative model of the multiple TCL1 targets explaining its oncogenic nature. Through a better functional characterization and the establishment of TCL1-centric therapeutic vulnerabilities we address a scientific knowledge gap on a common molecular denominator of CLL and T-PLL. The increasingly recognized role of TCL1 in features of stemness and solid tumor transformation broadens the significance spectrum of the envisioned studies of molecular concept-building and exploitation of actionable traits.


Dr. med. Marco Herling

CECAD / Dept. I of Internal Medicine

Dr. med. Marco Herling

Principal Investigator A 5

marco.herling@uk-koeln.de

Work +49 221 478 5194

Building 15
Kerpener Straße 62
50937 Cologne

http://cecad.uni-koeln.de/Dr-Marco-Herling.91.0.html

Publications - Marco Herling

Link to PubMed


Dr. rer. nat. Elena Vasyutina

CECAD / Dept. I of Internal Medicine

Dr. rer. nat. Elena Vasyutina

Co-Principal Investigator A 5

elena.vasyutina@uk-koeln.de

Work 0221 478 4130

Building 15
Kerpener Straße 62
50937 Cologne

Publications - Elena Vasyutina

Link to PubMed