The Critical Role of Inflammation in the Pathogenesis and Progression of Myeloid Malignancies

Abstract

Hematopoietic stem cells (HSCs) maintain an organism's immune system for a lifetime, and derangements in HSC proliferation and differentiation result in hematologic malignancies. Chronic inflammation plays a contributory if not causal role in HSC dysfunction. Inflammation induces HSC exhaustion, which promotes the emergence of mutant clones that may be resistant to an inflammatory microenvironment; this likely promotes the onset of a myeloid hematologic malignancy. Inflammatory cytokines are characteristically high in patients with myeloid malignancies and are linked to disease initiation, symptom burden, disease progression, and worsened prognostic survival. This review will cover our current understanding of the role of inflammation in the initiation, progression, and complications of myeloid hematologic malignancies, drawing from clinical studies as well as murine models. We will also highlight inflammation as a therapeutic target in hematologic malignancies.

Keywords: clonal hematopoiesis; hematopoietic stem cells; inflammation; myeloid malignancy; symptom burden.

Figure 1

Common upregulated pro- and anti-inflammatory cytokines in patient blood plasma or serum compared to healthy controls. Elevated tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6) are shared among the major myeloid malignancies. Cytokines in bold have been linked to prognostic survival in at least one hematopoietic malignancy. *Prognostic survival is correlated with transforming growth factor alpha (TGFα) only when IL-6 is also elevated. AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm. Referenced in [2,3,4,5,6,7,8,9]. EGF: epidermal growth factor; CXCL: chemokine (C-X-C motif) ligand; FGF: fibroblast growth factor; IL-1RA: interleukin 1 receptor antagonist; HGF: hepatocyte growth factor; IFNα: interferon alpha; CCL: chemokine (C-C motif) ligand; VEGF: vascular endothelial growth factor; G-CSF: granulocyte colony-stimulating factor; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinases; VCAM: vascular cell adhesion molecule.

Figure 2

Inflammatory cytokines are correlated with characteristic features of myeloid malignancies. Common symptoms of myeloid malignancies, especially of primary myelofibrosis, include fatigue, pruritus, loss of appetite, and vasomotor symptoms and are significantly correlated with inflammatory biomarkers. Splenomegaly, which is inherent to the biology of MPN is also associated with increased inflammatory cytokines as is thrombosis a common complication of MPN. Referenced in [30,47,48].

Figure 3

Model of clonal hematopoiesis in normal and inflammatory conditions. In a normal person, hematopoietic stem cells (HSCs) will differentiate and self-renew over the course of a lifetime to replenish the blood system. HSCs will acquire somatic mutations as a result of proliferative stress. Certain HSC mutant clones (i.e., Tet2, DNMT3A) will acquire a selective advantage over wild type (WT) HSCs, resulting in clonal hematopoiesis. However, in an inflammatory environment, normal HSCs are exhausted and have impaired fitness. HSCs will acquire somatic mutations and will likely have an accelerated selective advantage over the exhausted HSCs, resulting in an earlier onset of CHIP (not illustrated in figure) and possibly in hematologic malignancy.

Figure 4

Selective pressures may shape clonal expansion of mutant HSCs. During aging HSCs lose their self-renewal capacity as the cells continuously replenish the blood system. As a result, HSCs with mutations that skew towards self-renewal, such as Tet2 or DNMT3A, will have a selective advantage over aged HSCs [84,86]. However, in a person that previously received chemotherapy, HSC clones with different mutations will arise. Chemotherapy induces DNA damage in HSCs and activates DNA damage repair pathways or apoptosis. The incidence of HSCs with mutations in DNA damage repair pathways such as TP53 or PPM1D is significantly higher in people with previous chemotherapy treatment [66]. Specific pressures may allow for the expansion of less common mutations such as JAK2^V617F. MPN patients with JAK2^V617F mutations have elevated TNFα, contributing to the chronic inflammatory environment. Under chronic inflammation, normal HSCs will become exhausted and lose their competitive fitness, allowing for the emergence of mutant HSCs that are resistant to TNFα [85].