Emerging Insights into Molecular Mechanisms of Inflammation in Myelodysplastic Syndromes

Abstract

Inflammation impacts human hematopoiesis across physiologic and pathologic conditions, as signals derived from the bone marrow microenvironment, such as pro-inflammatory cytokines and chemokines, have been shown to alter hematopoietic stem cell (HSCs) homeostasis. Dysregulated inflammation can skew HSC fate-related decisions, leading to aberrant hematopoiesis and potentially contributing to the pathogenesis of hematological disorders such as myelodysplastic syndromes (MDS). Recently, emerging studies have used single-cell sequencing and muti-omic approaches to investigate HSC cellular heterogeneity and gene expression in normal hematopoiesis as well as in myeloid malignancies. This review summarizes recent reports mechanistically dissecting the role of inflammatory signaling and innate immune response activation due to MDS progression. Furthermore, we highlight the growing importance of using multi-omic techniques, such as single-cell profiling and deconvolution methods, to unravel MDSs' heterogeneity. These approaches have provided valuable insights into the patterns of clonal evolution that drive MDS progression and have elucidated the impact of inflammation on the composition of the bone marrow immune microenvironment in MDS.

Keywords: HSC; MDS; deconvolution; hematopoiesis; inflammation; sc-ATACseq; sc-RNAseq.

Figure 1

Inflammation impact on hematopoiesis (A,B). Hematopoietic stem cells (HSCs) in healthy bone marrow have the ability to self-renew and to differentiate into all blood cell lineages (A). Cytokines and chemokines are released from bone marrow microenvironment in response to stressors such as ageing, chronic inflammation, infections, and immune disorders (B). Prolonged or excessive exposure to these proinflammatory mediators can induce the loss of normal self-renewal HSCs capability and can lead to ineffective hematopoiesis. A common theme that has emerged from recent studies is that mutations in genes associated with CHIP (Clonal Hematopoiesis of Indeterminate Potential) and myeloid malignancies, such as Tet2 and Dnmt3a, render HSCs more susceptible to inflammation and chronic infections. In this scenario, the induction of HSCs clonal expansion due to inflammation contributes to sustained myelopoiesis and a more competitive advantage compared to that of normal cells.

Figure 2

Deconvolution workflow of bulk RNA-seq dataset from CD34 positive hematopoietic stem cells. Available sc-RNAseq datasets from CD34 positive cells from human bone marrows (1–3) are used to generate a signature matrix (4). In the second step, the deconvolution methods (7) require the expression profiles of CD34-positive mixed population (5–6) and the signature matrix (4) as input bulk data to estimate the abundance of cell types in each sample (8). FACS (Fluorescence-Activated Cell Sorting), HSC (Hematopoietic Stem Cell), MPP (MultiPotent Progenitor), CMP (Common Myeloid Progenitor), GMP (Granulocyte-Monocyte Progenitor), MEP (Megakaryocyte-Erythrocyte Progenitor), MLP (Multi-Lymphoid Progenitor), and PreB/NK (Pre-B cells and Natural Killer Cells).