Pathogenesis of angioimmunoblastic T-cell lymphoma

点击翻译按钮获取中文摘要

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most frequent T-cell lymphomas. It has a dismal prognosis, with most patients dying within three years after diagnosis. A unique feature of AITL is the frequent development of oligo- or monoclonal B-cell proliferations, sometimes giving rise to overt B-cell lymphomas. There is indication that mutations in the TET2 gene in AITL already occur in hematopoietic stem or precursor cells (HSC/HPC). In the first funding period, we established a method to perform whole exome sequencing from microdissected PD1-positive AITL tumor cells, and also performed whole genome sequencing from flow-sorted AITL cells. The evaluation of the first cases is currently under way. We also contributed to a targeted and exome sequencing analysis of AITL cases from formalin-fixed biopsies. By microdissection and PCR analysis of T and B cells from involved lymph nodes of 12 AITL cases we revealed that in most samples also a fraction of B cells carries the TET2 or IDH2 mutations present in the AITL clone. This confirms that these mutations typically occur in HSC/HPC, and shows that these mutated progenitor cells give also rise to TET2-mutated B cells. This might be one of the risk factors for the development of B-cell lymphomas in AITL patients. A detailed single cell IgV gene and TET2 mutation analysis of four selected AITL uncovered that the TET2-mutated B cells were mostly polyclonal B cells.In the second funding period, we aim to finish the exome and whole genome sequencing study of AITL to identify further genetic lesions and potential oncogenic viruses causing AITL. We will verify the pathogenetic role of selected mutated genes using an available mouse model (aim 1). As several recurrent mutations in AITL affect epigenetic regulators (TET2, IDH2, DNMT3A), we aim to characterize alterations of DNA methylation in AITL as a further pathogenetic principle in this disease (aim 2). We aim to establish cell lines from HSC/HPC of AITL patients and perform targeted and exome sequencing of these lines to reveal the pattern of genetic lesions already occurring at this early stage of AITL development (aim 3). We also aim to use such lines to determine the functional consequence of TET2 mutations on the DNA methylation and gene expression pattern of the HSC/HPC (aim 4). Finally, we plan to use targeted deep sequencing of AITL cases with concurrent or subsequent B-NHL to gain insight into the pathogenesis of such dual lymphomas by revealing the pattern of shared and distinct genetic lesions (aim 5). By determining the genetic and epigenetic landscape of AITL, their precursor cells and related B-NHL we aim to comprehensively characterize the multi-step transformation process in AITL in a mouse model as well as different cell populations from patients.