Cooperative progression of colitis and leukemia modulated by clonal hematopoiesis via PTX3/IL-1β pro-inflammatory signaling

Abstract Clonal hematopoiesis (CH) is considered an important risk factor for all-cause mortality and the development of multiple chronic diseases including hematological neoplasms, cardiovascular diseases, and potentially a range of autoimmune or immune-deficiency diseases. Mutations in TET2 are one of the first identified, most important, and prevalent genetic drivers of CH. However, cooperative factors and mechanisms underlying TET2 -deficiency related CH (TedCH) remain largely unknown. Recently, it has been suggested that certain diseases occurred before TedCH and promote TedCH trajectory on the contrary, indicating that diseases in non-hematopoietic organs may act as environmental non-genetic drivers of CH. To clarify the relationships between immune-dysfunctional diseases and CH, here we tested the impact of various challenges on TedCH. We found that expedited TedCH depended on establishment of an inflammatory environment. Primary or chimeric Tet2 -mutant mice spontaneously developed co-symptoms reminiscent of human chronic colitis and myeloid leukemia, which was exacerbated by feeding with DSS, an experimental inducer of ulcerative colitis. Single cell RNA-seq (scRNA-seq) analysis reveals in depth the damage of colon in the Tet2 -mutant mice in physiological conditions or fed with DSS, along with increase of dysbacteriosis indicated by gut microbiome analysis. Results from colon scRNA-seq from both mouse and human highlight the important roles of PTX3/IL-1β pro-inflammatory signaling in promoting colitis or leukemia. Finally, TedCH trajectory and inflammation in colon and bone marrow were ameliorated by treatment of IL-1R1 inhibitor Anakinra. Our study suggests that PTX3/IL-1β signaling and clonal hematopoiesis cooperate and play important roles in gut-bone marrow axis and related diseases including colitis and leukemia. Highlights Certain environmental factors, such as Dextran Sulfate Sodium (DSS), an experimental inducer of ulcerative colitis, promote TedCH Colitis and leukemia are spontaneously and simultaneously developed in Tet2 -defficient primary or chimeric mice, along with increased pathogenic gut microbiomes, indicating an aberrant gut-bone marrow axis in the mutant mice. Single cell RNA-seq analysis reveals enhanced PTX3, a soluble pattern recognition molecule and IL-1β pro-inflammatory signaling in colitis and leukemia. The In vivo function of the PTX3/IL-1β pro-inflammatory signaling in TedCH is indicated in human colitis and validated in experimental settings.