Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis

Abstract

Colorful clones in the blood Stem cells in regenerating tissues such as the blood can acquire mutations that enable a growth advantage, increasing the chance of developing cancer. It is unclear how such diverse mutations promote clonal fitness. Avagyan et al . generated a platform in zebrafish to label clones with unique hues while inducing mutations in genes implicated in human blood disorders. Mutations in some genes caused clones to expand over time, resulting in clonal dominance. Progenitors in the dominant clone expressed anti-inflammatory factors to resist the inflammatory environment produced by their own mature progeny, leading to a self-perpetuating cycle promoting clonal fitness. Targeting these resistance pathways may be used to abate clonal hematopoiesis and prevent its associated pathology. —BAP

Deciphering TP53 mutant Cancer Evolution with Single-Cell Multi-Omics

“…Inflammation is a cardinal regulator of HSC function with many effects on HSC fate and function 39 , including proliferation-induced DNA-damage and depletion of HSC 40 . There is emerging evidence that clonal HSC can become inflammation-adapted 39, 41, 42 and by altering the response to inflammatory challenges, mutations can thus confer a fitness advantage to HSC. Here, we demonstrate a hitherto unrecognized effect of TP53 mutations, which conferred a marked fitness advantage to HSPC in the presence of chronic inflammation, which we speculate could occur by altering the HSC response to proliferation-induced DNA-damage.…”

Aging and Clonal Behavior of Hematopoietic Stem Cells

“…This system is quite useful for visualizing the clonal behavior of tissue-specific stem and progenitor cells in the solid organs, such as the brain and intestine [42], and similar attempts have been made to evaluate HSC clonal behavior after transplantation or during aging [9,43]. Interestingly, by combining genetic color-coding of zebrafish mesoderm with the CRISPR-Cas9-mediated mutagenesis of several clonal hematopoiesis-related genes, Zon and colleagues have recently demonstrated the clonal expansion of Asxl1-mutant HSCs, with the support of an inflammatory environment [44]. However, since hematopoietic tissues are not compartmentalized like the intestine and the ability to distinguish individual clones is hampered due to spectrum overlapping, the visualization of clonal architecture of hematopoiesis by multicolor fluorescence remains relatively challenging.…”

Nonresolving inflammation redux

“…Inflammation can skew hematopoietic stem cells toward myelopoiesis, and increased numbers of myeloid cells can promote further inflammation ( Chavakis et al., 2019 ). Inflammatory suppression of hematopoiesis can help select for the emergence of clones better able to withstand it ( Avagyan et al., 2021 ; Caiado et al., 2021 ; Trowbridge and Starczynowski, 2021 ). Some of these clones may give rise to myelodysplastic syndrome or leukemia.…”