Il-1r1 drives leukemogenesis induced by Tet2 loss

Burns, Sarah; Kumar, Ramesh; Kumar, Palanisamy Mahesh; So, Kaman; Zhang, Chi; Kapur, Reuben

doi:10.1038/s41375-022-01665-3

Cited by 22 publications

(13 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with previous studies (Burns et al, 2022; Caiado et al, 2023), in the context of DSS challenged-TedCH, our data suggest that anakinra eliminates the Tet2 +/- clones in the clonal expansion in neutrophil and HSPC compartments, inhibits gut inflammation, and restores the adaptive hematopoietic injury induced by chronic inflammation. However, it does not fully restore the established clonal dominance in the HSPC pool, which may be partially addressed by increasing the treatment dose and duration.…”

Section: Discussionsupporting

confidence: 92%

“…Microbial signals are a major source of inflammatory inducer and interestingly Tet2 mutant mice with antibiotic treatment or raised in germ-free condition developed minimal CMML-like phenotypes (Meisel et al, 2018). In line with these studies, a most recent study based on in vivo models rather than generating chimeric Tet2 -mutant models demonstrated that interleukin-1 (IL-1α and IL-1β), is able to act as an external factor in driving Tet2 -deficiency related clonal hematopoiesis (TedCH) over age; genetic loss of their receptor IL1-R1 mitigated Tet2 -deficiency related abnormalities (Burns et al, 2022; Caiado et al, 2023). In summary, results from several independent studies strongly suggest that Tet2 -deficient HSPCs manifest TedCH phenomenon and cooperate with intrinsic and extrinsic factors to develop stronger symptoms such as full-blown leukemia AML.…”

Section: Introductionmentioning

confidence: 90%

See 1 more Smart Citation

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

He,

Wen,

et al. 2023

Preprint

View full text Add to dashboard Cite

Clonal hematopoiesis (CH) is suggested as an important risk factor for all-cause mortality and multiple chronic diseases including hematological neoplasms, cardiovascular diseases, and potentially a spectrum 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. Controversially, it is recently suggested that certain diseases take place prior to TedCH and promote TedCH on the contrary, indicating diseases in non-hematopoietic organs may act as environmental non-genetic drivers of CH. To clarify relationships between immune-dysfunctional diseases and CH, here we tested impact of various challenges on TedCH. We found that expedited TedCH depended on establishment of 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 and bone marrow in the Tet2-mutant mice in physiological condition 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 important roles of PTX3/IL-1β pro-inflammatory signaling in promoting colitis or leukemia. Finally, TedCH trajectory and inflammation in colon and bone marrow was ameliorated by treatment of IL-1R1 inhibitor Anakinra. Our study suggests that PTX3/IL-1β signaling and clonal hematopoiesis cooperates and plays important roles in gut-bone marrow axis and related diseases including colitis and leukemia.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 90%

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

He,

Wen,

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…LSKs trended towards elevation in the spleen of Tet2 -KO relative to WT (p = 0.06), while this elevation is reduced in DKO relative (Supplementary Fig. 8c) as has been observed previously (44). Within MPPs, MPP3s were overrepresented in Tet2 -KO and MPP4s were underrepresented, while these changes are less pronounced in DKO mice (Supplementary Fig.…”

Section: Resultssupporting

confidence: 84%

“…This is consistent with recent findings, in which genetic deletion of interleukin 1 receptor 1 ( Il1r1) has been implicated to rescue premalignant phenotypes of the Tet2 -KO mice at 10 months (40. 5 weeks) of age (44).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The transcriptional and epigenetic reprogramming associated with chronic IL1β-mediated expansion and myeloid priming in TET2 deficient stem and progenitor cells

McClatchy¹,

Strogantsev²,

Wolfe³

et al. 2022

Preprint

View full text Add to dashboard Cite

Clonal hematopoiesis (CH) increases risk for the development of hematological malignancy and cardiovascular disease. IL1β is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models with Tet2 loss-of-function. How IL1β alters population dynamics of hematopoietic cells upon Tet2 deletion (Tet2-KO) is not well understood. We demonstrated IL1β expands Tet2-KO neutrophils, monocytes/macrophages, and long-term hematopoietic stem cells with reduced lymphopoiesis. IL1β promoted myeloid bias over other lineages of Tet2-KO HSPCs coinciding with failure to demethylate lineage associated enhancer and transcription factor binding sites. IL1β enhanced the self-renewal ability of Tet2-KO HSPCs by upregulating genes associated with self-renewal potential and by resisting demethylation of binding sites of transcription factors promoting terminal differentiation. IL1β-mediated premalignant phenotype is reversed by IL1β antagonist anakinra or deletion of the Il1 receptor, in vivo. Our results demonstrated that targeting IL-1 signaling could be an efficient early intervention strategy in preleukemic disorders.

show abstract