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-1{beta} 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-1{beta} signaling and clonal hematopoiesis cooperate and play important roles in gut-bone marrow axis and related diseases including colitis and leukemia. HighlightsO_LICertain environmental factors, such as Dextran Sulfate Sodium (DSS), an experimental inducer of ulcerative colitis, promote TedCH C_LIO_LIColitis 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. C_LIO_LISingle cell RNA-seq analysis reveals enhanced PTX3, a soluble pattern recognition molecule and IL-1{beta} pro-inflammatory signaling in colitis and leukemia. C_LIO_LIThe In vivo function of the PTX3/IL-1{beta} pro-inflammatory signaling in TedCH is indicated in human colitis and validated in experimental settings. C_LI