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. 2023 Apr 26;13:1177590. doi: 10.3389/fonc.2023.1177590

Figure 1.

Figure 1

Integrative biologic model for AITL pathogenesis. AITL development follows a “multi-step” process. The initiating event of neoplasia (“first-hit”) involves age-related mutations in epigenetic regulatory genes (TET-2 and/or DNMT3A) that compromise the pluripotent hematopoietic stem cells-CD34+ with propagation to myeloid precursor cells, B- and T-lymphoid cells. Subsequently, the naïve T-CD4+ cell matures to TFH-cell in the germinal center and experiences specific-disease (“driver”) mutations, such as the RhoA G17V and/or IDH-2 R172 K/S (“second-hit”). Finally, mature and mutated TFH-cells expand in the germinal center from the interaction with several elements of the tumor immune microenvironment (FDC, macrophages, B-cells, endothelial-cells and EBV), which provide an environment marked by immune-dysregulation and pro-inflammatory activity, highly permissive for the propagation and dissemination of the neoplasm (“third -hit”).