The Role of Inflammation in the Initiation and Progression of Myeloid Neoplasms

Abstract

Myeloid malignancies are devastating hematologic cancers with limited therapeutic options. Inflammation is emerging as a novel driver of myeloid malignancy, with important implications for tumor composition, immune response, therapeutic options, and patient survival. Here, we discuss the role of inflammation in normal and malignant hematopoiesis, from clonal hematopoiesis to full-blown myeloid leukemia. We discuss how inflammation shapes clonal output from hematopoietic stem cells, how inflammation alters the immune microenvironment in the bone marrow, and novel therapies aimed at targeting inflammation in myeloid disease.

Significance: Inflammation is emerging as an important factor in myeloid malignancies. Understanding the role of inflammation in myeloid transformation, and the interplay between inflammation and other drivers of leukemogenesis, may yield novel avenues for therapy.

Figure 1.

Inflammation: a tumor kernel. Inflammation has been described as a hallmark of cancer since 2009. Here, we present inflammation as an instigator of cancer that affects (directly or indirectly) all other tumor hallmarks.

Figure 2.

Inflammatory pathways in the hematopoietic system and BM niche components. Within the BM, HSC, progenitors, and committed precursors express a battery of cytoplasmic and cell-surface receptors to detect microbial components and inflammatory cytokines. Similarly, the BM niche and accessory cells possess several sensors and can release high levels of inflammatory cytokines to shape immune responses at the central level of hematopoiesis. Here we highlight the major cytokines and sensors expressed in the BM stromal compartment and throughout hematopoietic differentiation (Created with BioRender.com). Ach, acetylcholine; Ang-1, angiopoietin 1; CAR, CXCL12-abundant reticular; CDP, common dendritic progenitor; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; DC, dendritic cell; ETP, early T-cell precursor; G-CSF, granulocyte colony stimulating factor; GMP, granulocytic-monocytic progenitor; GP, granulocytic precursor; HSC, hematopoietic stem cell; ILC, innate lymphoid cell; MDP, monocytic-dendritic precursor; MPP, multipotent progenitor; MEP, megakaryocytic and erythroid progenitor; MSC, mesenchymal stromal/stem cell; NE, norepinephrine; NK, natural killer; Opn, osteopontin; SCF, stem cell factor; TPO, thrombopoietin.

Figure 3.

Common myeloid mutations and their inflammatory milieu. Normal HSC are supported by the BM stroma. Mutated HSC (or their progeny) produce inflammatory factors that can activate the BM niche to produce more inflammatory factors creating positive feedback loops. Clinical observations and experimental data have shown that mutations observed CH have different inflammatory profiles and are better sustained by different context niches (Created with BioRender.com).

Figure 4.

BM dynamics during aging and acute/chronic inflammation. Homeostatic hematopoiesis occurs in the BM and maintains a balance of mature immune cells. Emergency hematopoiesis is a process of rapid proliferation of HSPC due to an insult, which is rapidly resolved. The increased levels of ROS and inflammation may induce silent mutations in HSPC, which can be restricted by different checkpoints (repair mechanisms, immunosurveillance, repressor niches). Sustained inflammation may reprogram HSPC and the BM niches. Physiologic aging is associated with increased systemic levels of inflammatory cytokines (inflammaging) and erosion of the BM niche. The protumoral niches sculpting during chronic inflammation or aging and immune editing may create neighborhoods that allow the selection of mutant clones (Created with BioRender.com).

Figure 5.

Targeting inflammation in myeloid neoplasms. Novel therapeutic strategies are emerging to target inflammatory pathways in myeloid neoplasms. Ongoing clinical trials include small molecules and neutralizing antibodies. Novel studies are suggesting the efficacy of some splicing inhibitors or the use of immune-checkpoint blockers in patients with high levels of inflammation showing exhausted and/or anergic immune cells. Future therapeutic options may include targeting the inflamed niche and eliminating fibrosis; achieving repression of CH will be a major milestone for preventative medicine (Created with BioRender.com).