The Role of Inflammatory Signaling Pathways in TET2-Deficient Hematological Malignancies

Abstract

Loss of the TET2 gene, which is commonly mutated in the pre-leukemic condition clonal hematopoiesis of indeterminate potential (CHIP) and hematological malignancies, dysregulates inflammation, including the interleukin-1 (IL-1) and interleukin-6 (IL-6) pathways. As TET2 mutations are often present in hematopoietic stem and progenitor cells, dysregulation of these pathways may contribute to leukemogenesis and may catalyze the progression of pre-leukemic states, such as CHIP, to malignancy. Tet2-/- mice exhibit splenomegaly, myeloid expansion, and myeloid malignancy. To investigate the effects of inactivation of IL-1 receptor, type 1 (Il-1r1) and Il-6 on Tet2-deficient mature and immature hematopoietic cells, Tet2-/-;Il-1r1-/- and Tet2-/-;Il-6-/- mice were generated. Interestingly, Il-1r1 loss rescued the leukemic phenotypes associated with Tet2 inactivation, including expansion of myeloid cells, suppression of lymphoid cells, and restoration of spleen size. These phenotypes were recapitulated with competitive transplant, suggesting that IL-1R1 exerts a cell autonomous role. Mice transplanted with Tet2-/-;Il-1r-/- bone marrow cells exhibited differential regulation of specific myeloid and lymphoid subpopulations. At the stem-cell level, the frequencies of early myeloid Lin-;c- Kit+, early lymphoid Lin-;Sca1+ progenitors, and multipotent progenitor populations 2 and 3/4 were corrected, and a pronounced and reciprocal switch in the levels of Lin-;c- Kit+ and Lin-;Sca1+ cells was detected. Aged Tet2-/-;Il-1r-/- mice retained some of these phenotypes. Acute myeloid leukemia with higher IL-1R1 expression had reduced survival, indicating potential clinical implications. Similar to Tet2-/-;Il-1r1-/- mice, Tet2-/- ;Il-6-/- mice showed correction of myeloid cell expansion and lymphocyte suppression; however, they also demonstrated a significant increase in long-term hematopoietic stem cells and possible splenic extramedullary hematopoiesis, highlighting unique roles of IL- 6 in the pre-leukemic context. Collectively, these findings suggest that IL-1R1- and IL-6- dependent signaling exhibit overlapping functions but also have distinct roles in leukemogenesis that may have important implications for the clinical management of CHIP and hematological malignancies.