Fig. 1: Proposed concept of T-LGLL pathogenesis.

This schematic overview illustrates the pathobiological landscape of T-LGLL, highlighting key genomic, transcriptomic, and microenvironmental factors that drive T-LGLL leukemogenesis. The proposed initial event for T-LGLL is a chronic antigenic stimulation, resulting in polyclonal LGL expansion. The expansion of LGLs is further supported by inflammatory cytokines, like IL-2, IL-6, and IL-15, potentially secreted by the non-leukemic compartment, like B-cells, CD4⁺ T cells, monocytes, and other antigen-presenting cells (APC). Autocrine platelet-derived growth factor (PDGF)-BB signaling, via PI3K/Akt/mTOR, adds an additional proliferative stimulus. Clonal selection of T-LGLL expansions can be further favored by the occurrence of specific mutations, predominantly gain-of-function (GOF) mutations of STAT3 in CD8⁺ T-LGLL and STAT5B in CD4⁺ T-LGLL. Constitutive activation of STAT3 is additionally achieved by diminished expression of the negative regulator SOCS3. Pathways conferring resistance to apoptosis are also shown, with increased c-FLIP levels contributing to Fas/FasL resistance. Red shadows indicate proven alteration within T-LGLL cells; dashed arrows show suspected but unconfirmed interactions, while gray arrows denote downregulated effects in T-LGLL. The figure was created with Biorender.