Inflammatory bone marrow microenvironment

Abstract

Self-renewing hematopoietic stem cells and their progeny, lineage-specific downstream progenitors, maintain steady-state hematopoiesis in the bone marrow (BM). Accumulating evidence over the last few years indicates that not only primitive hematopoietic stem and progenitor cells (HSPCs), but also cells defining the microenvironment of the BM (BM niche), sense hematopoietic stress signals. They respond by directing and orchestrating hematopoiesis via not only cell-intrinsic but also cell-extrinsic mechanisms. Inflammation has many beneficial roles by activating the immune system in tissue repair and as a defense mechanism. However, chronic inflammation can have detrimental effects by stressing HSPCs, leading to cell (DNA) damage resulting in BM failure or even to leukemia. Emerging data have demonstrated that the BM microenvironment plays a significant role in the pathogenesis of hematopoietic malignancies, in particular, through disrupted inflammatory signaling, specifically in niche (microenvironmental) cells. Clonal selection in the context of microenvironmental alterations can occur in the context of toxic insults (eg, chemotherapy), not only aging but also inflammation. In this review, we summarize mechanisms that lead to an inflammatory BM microenvironment and discuss how this affects normal hematopoiesis. We pay particular attention to the process of aging, which is known to involve low-grade inflammation and is also associated with age-related clonal hematopoiesis and potentially malignant transformation.

Secondary CNL after SAA reveals insights in leukemic transformation of bone marrow failure syndromes

“…These results corroborate the important role of inflammatory signaling pathways in preleukemic stem cells, particularly in the context of secondary leukemia, 30,31 and may suggest that an inflammatory BM environment in which the SAA-and SCN-mutant CD34 high HSPCs reside contribute to a permissive condition for the development of leukemic cells. 32,33 In summary, this patient with CNL evolving from SAA provides unique insights into potentially important mechanisms of leukemic transformation of BM failure syndromes. The molecular similarities with SCN and the resembling transcriptional profiles corroborate the role of inflammatory signaling pathways in preleukemic and leukemic stem cells, particularly in the context of secondary leukemia.…”

Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia

“…Detected both systemically and in the BM stroma, inflammation is an important event during aging and can alter hematopoiesis ( Kovtonyuk et al., 2016 ; Helbling et al., 2019 ). As inflammation can contribute to cancer pathogenesis, one possible explanation for the development of DDL from CHIP donors is that hematopoietic lineages exhibiting pro-inflammatory phenotypes may modify the BM microenvironment and hematopoiesis to promote leukemogenesis ( Figure 2 ) ( Henry et al., 2015 ; Leimkuhler and Schneider, 2019 ). For example, chronic exposure to IL-1 reduces HSPC self-renewal capacity, skews differentiation toward myeloid lineages, hinders transplantation, and contributes to hematological malignancy ( Pietras et al., 2016 ; Arranz et al., 2017 ).…”

“…Inflammation in the BM microenvironment can also cause DNA damage, which may drive the acquisition of additional mutations that can promote DDL ( Wiseman, 2011 ; Leimkuhler and Schneider, 2019 ). Inflammation in BM stromal cells exacerbates genotoxic stress and promotes progression of preleukemic conditions ( Zambetti et al., 2016 ).…”

Putative Mechanisms Underlying Cardiovascular Disease Associated with Clonal Hematopoiesis of Indeterminate Potential

“…In addition to promoting the expansion of clones carrying CHIP-associated mutations, inflammation can also alter the BM microenvironment ( Leimkuhler and Schneider, 2019 ). Inflammation and the BM microenvironment change with age, influencing the context in which CHIP-associated inflammation occurs ( Ho et al., 2019 ; Kovtonyuk et al., 2016 ).…”