Activation of distinct inflammatory pathways in subgroups of LR-MDS

Abstract

Aberrant innate immune signaling has been identified as a potential key driver of the complex pathophysiology of myelodysplastic neoplasms (MDS). This study of a large, clinically and genetically well-characterized cohort of treatment-naïve MDS patients confirms intrinsic activation of inflammatory pathways in general mediated by caspase-1, interleukin (IL)-1β and IL-18 in low-risk (LR)-MDS bone marrow and reveals a previously unrecognized heterogeneity of inflammation between genetically defined LR-MDS subgroups. Principal component analysis resolved two LR-MDS phenotypes with low (cluster 1) and high (cluster 2) levels of IL1B gene expression, respectively. Cluster 1 contained 14/17 SF3B1-mutated cases, while cluster 2 contained 8/8 del(5q) cases. Targeted gene expression analysis of sorted cell populations showed that the majority of the inflammasome-related genes, including IL1B, were primarily expressed in the monocyte compartment, consistent with a dominant role in determining the inflammatory bone marrow environment. However, the highest levels of IL18 expression were found in hematopoietic stem and progenitor cells (HSPCs). The colony forming activity of healthy donor HSPCs exposed to monocytes from LR-MDS was increased by the IL-1β-neutralizing antibody canakinumab. This work reveals distinct inflammatory profiles in LR-MDS that are of likely relevance to the personalization of emerging anti-inflammatory therapies.

Emerging Insights into Molecular Mechanisms of Inflammation in Myelodysplastic Syndromes

“…This evidence has been recently confirmed in a large cohort of MDS patients [24]. In this study, inflammatory pathways mediated by caspase-1, interleukin-1b, and interleukin-18 have been identified in low-risk MDS (LR-MDS) bone marrow patients [24]. Bulk RNA-seq experiments revealed a previously unrecognized heterogeneity of inflammation in these patients, as two different phenotypes with different levels of IL-1b were identified [24] (Table 1).…”

“…Specifically, increased levels of proinflammatory cytokines, reactive oxygen species, and alarmins induced the NF-kB-driven expression of key inflammasome components, such as NLRP3, PYCARD (pyrin domain and caspase recruitment domain), and caspase-1, as well as prointerleukin-1b and pro interleukin-18 [40]. This evidence has been recently confirmed in a large cohort of MDS patients [24]. In this study, inflammatory pathways mediated by caspase-1, interleukin-1b, and interleukin-18 have been identified in low-risk MDS (LR-MDS) bone marrow patients [24].…”

“…In this study, inflammatory pathways mediated by caspase-1, interleukin-1b, and interleukin-18 have been identified in low-risk MDS (LR-MDS) bone marrow patients [24]. Bulk RNA-seq experiments revealed a previously unrecognized heterogeneity of inflammation in these patients, as two different phenotypes with different levels of IL-1b were identified [24] (Table 1). These two different groups of patients were characterized by different mutational profiles, as one cluster contained 14/17 SF3B1-mutated cases, while the other cluster contained 8/8 del(5q) cases [24].…”

“…Bulk RNA-seq experiments revealed a previously unrecognized heterogeneity of inflammation in these patients, as two different phenotypes with different levels of IL-1b were identified [24] (Table 1). These two different groups of patients were characterized by different mutational profiles, as one cluster contained 14/17 SF3B1-mutated cases, while the other cluster contained 8/8 del(5q) cases [24]. Moreover, the gene expression of sorted cell populations showed that the majority of the inflammasomerelated genes, including IL-1b, were mainly expressed in the monocyte compartment [24].…”

“…These two different groups of patients were characterized by different mutational profiles, as one cluster contained 14/17 SF3B1-mutated cases, while the other cluster contained 8/8 del(5q) cases [24]. Moreover, the gene expression of sorted cell populations showed that the majority of the inflammasomerelated genes, including IL-1b, were mainly expressed in the monocyte compartment [24]. This result confirms the dominant role of these cells in determining the bone marrow environment in MDS.…”