Understanding how clonal hematopoiesis feeds lymphoma
Worldwide Cancer Research
Institute of Oncology Research
As the fifth most frequently occurring cancer type in humans, lymphoma still requires to be mechanistically better understood in order to achieve a satisfactory relative survival. A promising approach to close this knowledge gap concerning lymphoma consists in investigating the microenvironment and potentially occurring inflammatory processes, which may have a supportive effect on the emerging and maintenance of tumor progression. Clonal hematopoiesis (CH) is the accumulation of mutations in the myeloid-monocyte lineage in healthy individuals. CH has been correlated with inflammation and aging of immune response. One of the most-common mutations in CH is loss-of-function alleles in TET2. TET2 encodes an enzyme involved in epigenetic regulation of hematopoietic cells. Our working hypothesis is that TET2 mutated CH creates an inflamed niche of myeloid cells that support the tumor and/or impair the anti-tumor immune response. Our working hypothesis will be addressed through distinct tasks: 1.) Provide experimental proof that TET2 mutated myeloid cells are enriched in the intra-tumoral microenvironment of lymphoma patients with CH, and that they have a pro-inflammatory/tumor supportive phenotype; 2.) Validating that Tet2–deficient hemopoiesis promotes lymphoma development and 3.) Proofing that TET2 mutated CH is an unfavorable prognostic biomarker in lymphoma. The project leverage state-of-the-art and novel single cell technologies, novel strains of genetically modified mouse models of lymphoma, and clinical trial cohorts. The project will impact on our understanding of lymphoma biology and will create a new platform for therapeutic advances in this tumor. In terms of knowledge, we will discover a completely new and actionable mechanism of lymphoma promotion that may be termed as “monoclonal immune microenvironment” that will advance the understanding of the interplay between immune-aging and tumor development. In terms of treatment, we will generate both reagents and candidate targets from pre-clinical studies aiming at re-educating or eradicating the “monoclonal immune microenvironment”.
2.1 Biological and endogenous factors