Ontogeny and oncogenic potential of genetic alterations in peripheral T-cell lymphomas

• Applicant: Privatdozent Dr. Raphael Koch
• Subject Area: Hematology, Oncology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267789924

Peripheral T-cell lymphomas (PTCLs) are a diverse family of lymphoid neoplasms with poor prognosis. PTCLs represent approximately 6-10% of non-Hodgkin lymphomas and include multiple distinct biologic subtypes with variable clinical behavior. In Europe and North America, PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) are the most common entities. Treatment regimens are analogous to B-cell lymphomas but show inferior outcomes. Thus there is an urgent need for a better understanding of the genetic background of PTCLs to develop new and more effective therapies.Recent studies, including whole genome, exome and transcriptome sequencing have provided initial insights into genetic alterations in some T-cell lymphomas but have not clarified molecular pathogenesis of PTCLs or identified new therapeutic targets.The aim of this project is to elucidate the prevalence of recurrent genetic mutations in PTCLs and the timing and cellular context during which these alterations occur (ie, the molecular ontogeny). Defining the molecular ontogeny of PTCLs is likely to elucidate new targets for both malignant and premalignant cells, offering new strategies to block essential stages of lymphomagenesis. These genetic data will be used to determine the contribution of patient-derived PTCL genotypes to lymphomagenesis in vitro. We will perform genotyping of PTCL specimens using targeted exon capture followed by deep sequencing to identify recurrent mutations. To define the ontogeny of these mutations, we will flow sort peripheral blood stem cells (PBSCs) from patients after sequencing of their lymphomas. We will extract DNA from hematopoietic stem cells (HSCs) as well as myeloid, B- and T-lineage progenitors, and then subject these fractions to ultra-deep sequencing at sites known to be mutated in their lymphomas. This will create a 2-dimensional (lineage vs. differentiation hierarchy) map for each case of mutation acquisition that leads to PTCL. The oncogenic potential of newly-identified patient-derived mutations will be elucidated using a cDNA library screen, applied to the cytokine-dependent cell lines Ba/F3 and MOHITO.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. David M. Weinstock