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Mastocytosis, a disorder characterized by the accumulation of abnormal mast cells, presents a significant diagnostic challenge for clinicians due to its wide range of clinical manifestations and varying prognosis. That said, new research suggests a potential tool for refining diagnoses and understanding the diverse clinical manifestations of mastocytosis.^1,2 Serum tryptase levels are currently used to aid in diagnosis, but this marker is not specific to mastocytosis and does not always accurately reflect disease severity.³ A new study by Cristina Iribarren, PhD, and colleagues published in The Journal of Molecular Diagnostics suggests that analyzing a panel of plasma proteins could help to distinguish between indolent and advanced forms of systemic mastocytosis (SM), potentially leading to more precise diagnoses and personalized treatment approaches.¹

Accurately diagnosing and classifying mastocytosis is essential for determining the most effective treatment strategy. While certain types of SM follow a relatively benign course, others, known collectively as advanced systemic mastocytosis (AdvSM), are associated with a more aggressive progression and worse prognosis.⁴ The clinical heterogeneity of SM, ranging from mild skin involvement to life-threatening organ damage, further complicates diagnosis and treatment decisions.² This underscores the need for more refined diagnostic tools that can accurately distinguish between subtypes and predict disease course.¹

The current study investigated whether analyzing the levels of various proteins circulating in the blood could provide a more accurate picture of mastocytosis subtype and disease activity. Researchers used a technique called Proximity Extension Assay technology to measure the levels of 275 different proteins in plasma samples from 108 adult patients with mastocytosis. Included were patients classified as having cutaneous mastocytosis [CM] (16), indolent systemic mastocytosis [ISM] (80), or AdvSM (12) and 60 patients with polycythemia vera, who served as a reference group.¹

Unveiling protein signatures and differentiating among mastocytosis subtypes

The analysis revealed distinct patterns of protein levels in the blood of patients with different mastocytosis subtypes. Using a statistical technique called principal component analysis, researchers were able to clearly separate patients with CM and ISM from those with AdvSM based on their unique protein profiles.¹ This finding suggests that the underlying biological processes driving these subtypes may be reflected in the circulating proteins, potentially offering a more precise way to classify patients than currently available methods.

The researchers identified several proteins, including IL-1RT1, LAG3, TNFSF13B, EGLN1, and IL-18BP, which were present at significantly higher levels in the blood of patients with AdvSM compared to those with ISM, suggesting these proteins may play a role in the more aggressive disease process observed in AdvSM.¹ Importantly, these distinct protein profiles were also observed when comparing patients with SM to those with polycythemia vera, suggesting that the identified proteins are specific to mastocytosis rather than a general marker of blood disorders.¹

Beyond mast cells

To further investigate the cellular origins of the identified proteins, researchers used single-cell RNA sequencing (scRNA-seq), which allows for the analysis of the gene expression patterns of individual cells, providing insight into which cell types are producing specific proteins. The scRNA-seq analysis revealed that the proteins associated with mastocytosis were not exclusively produced by mast cells, but also by other immune cells present in the bone marrow.¹ This finding highlights the complex interplay of various cell types in the pathogenesis of mastocytosis and suggests that targeting a single cell type may not be sufficient for effective treatment.¹

Caveats

While promising, the study has some limitations. The sample size, particularly for the AdvSM group, was relatively small, and further research with larger cohorts is needed to validate the findings.¹ Additionally, the study was conducted at a single center in Sweden, and the results may not be generalizable to all populations.¹

Implications for clinical practice

Despite the limitations, this research highlights the potential of plasma protein profiling as a valuable tool for refining mastocytosis diagnoses, potentially allowing clinicians to more accurately distinguish between indolent and advanced forms of the disease. This information could guide treatment decisions, helping to ensure that patients receive the most appropriate and effective therapies. As the authors note, "[d]istinct plasma protein profiles show potential to refine ISM and AdvSM diagnoses, possibly reflecting differences in pathogenic mechanisms and diverse clinical manifestations."¹

Future studies should focus on validating these findings in larger, more diverse patient populations and exploring the clinical utility of these protein biomarkers for predicting disease progression, monitoring treatment response, and ultimately guiding the development of targeted therapies for mastocytosis.

Published: August 28, 2024