How Inflammation Factors May Influence Lower-Risk MDS

Researchers are coming closer to finding out precisely how inflammation may be connected to myelodysplastic syndromes (MDS). Learning about their relationship, by analyzing inflammatory biomarkers and pathways in patients with low-risk MDS, could point the way to developing future MDS therapies, wrote authors in the British Journal of Haematology.¹

This team developed a novel approach to measure quantities of ASC/NLRP3 protein specks—which are specific only for the NLRP3 inflammasome—and combined that methodology with measuring a range of inflammatory cytokines.

Activation of the NLRP3 inflammasome catalyzes the release of proinflammatory cytokines interleukin (IL)-1β and IL-18, and they, along with IL-6, tumour necrosis factor (TNF) α, and IL-8 have all been shown to directly support the growth of aberrant MDS stem cells in preclinical models, explained the authors. Their study results, they noted, add to the evidence that autoinflammation—particularly dysregulation of the innate immune response—may play an important role in MDS pathogenesis.²

Patients with lower-risk MDS have limited treatment options, and inflammatory pathways are potential targets| Image Credit: cacaroot-stock.adobe.com

Patients with lower-risk MDS currently have limited treatment options, and if selected inflammatory pathways could be therapeutically targeted, blood counts could potentially be improved and the risk of disease progression reduced.

More Than a Speck of Evidence

The researchers found that ASC/NLRP3 specks were significantly elevated in patients who have MDS compared with healthy controls (P < .001). For the first time, these levels were comparable with those found in patients with autoinflammatory disorders, whose data were also examined. The investigators’ goal was to determine how such measurements could help predict the risks for transfusion dependency, transformation to acute myeloid leukemia, and overall survival.

The team’s MDS cohort included 183 patients with low bone marrow blasts (< 5%) for whom they had available long-term outcome data.

The distribution of protein specks positive only for ASC was different than that of those positive for ASC/NLRP3. Other ASC-containing inflammasome complexes might be significant in MDS pathogenesis, the authors hypothesized. ASC is also “an important adaptor for a range of other inflammasomes, including NLRP1, AIM2, Pyrin, NLRC4, and newly discovered NLRP10,” the team pointed out.

Patients with MDS had significantly higher levels of IL-18, IL-33, IL-23, IL-6, IL-8, interferon (IFN) γ, and IFN-α2, compared with healthy controls; the levels were comparable with those of patients with autoinflammatory disorders. The result that the level of activation of NLRP3 in patients with MDS was comparable with what is seen in classical autoinflammatory disorders supports the hypothesis that additional non-NLRP3, ASC-containing inflammasomes might have a role in MDS pathogenesis.

Further evidence for the hypothesis is the finding that IL-6 and IL-18 levels were significantly elevated in the MDS cohort compared with healthy controls. IL-18 “is directly linked to NLRP3 inflammasome activation, but it is also released following NLRC4 activation, which favors IL-18 over IL-1β,” they noted.

The team found also that TNFα was positively associated with MDS progression to a more aggressive form of disease, and IL-6 and IL-1β were associated with time to first red blood cell transfusion in patients with MDS. Targeted cytokine blockade thus might be beneficial to modulate MDS evolution or prevent certain MDS complications, they said.

The authors are continuing their work, using large cohorts of patients with low-risk MDS for whom complete clinical and molecular characterization is available. This work, and that of colleagues, they stated, will continue to pinpoint the potential role of ASC/NLRP3, and other inflammatory markers, in disease stratification, making prognoses, and directing treatment decisions.

References

1. Topping J, Taylor A, Nadat F, et al.Inflammatory profile of lower risk myelodysplastic syndromes. Br J Haematol. Published online May 21, 2024. doi:10.1111/bjh.19530

2. Kouroukli O,Symeonidis A,Foukas P,Maragkou MK,Kourea EP.Bone marrow immune microenvironment in myelodysplastic syndromes.Cancers (Basel).2022;14(22):5656. doi:10.3390/cancers14225656