Plasma protein profiling to discern indolent from advanced systemic mastocytosis

Abstract

Mastocytosis is a heterogeneous disorder characterized by abnormal mast cell accumulation, in which the clinical severity may be explained by distinct molecular mechanisms. This study aimed to explore plasma protein biomarkers associated with systemic mastocytosis subtypes, as well as the cellular origin of the identified proteins. Plasma samples from patients with mastocytosis, including cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), advanced SM (AdvSM), and a reference group of patients with polycythemia vera (PCV), were analyzed by Proximity Extension Assay (OLINK technology) targeting 275 proteins. Furthermore, potential cellular origin was explored using an available scRNA sequencing data set generated from ISM patients. The study cohort included 16 patients with CM, 92 patients with SM (ISM, n=80; AdvSM, n=12), and 60 PCV patients. A Principal Component Analysis based on 275 plasma proteins revealed one cluster of CM and ISM patients that was separated from AdvSM patients. Up to 29 proteins were associated to distinct severe activity in SM patients (ISM vs AdvSM), including IL-1RT1, and TNFSF13B (q<0.01). Furthermore, scRNA seq analysis from ISM-derived bone marrow cells revealed that the mRNA for the identified proteins was not exclusive of mast cells. Distinct plasma protein profiles show potential to refine ISM and AdvSM diagnoses, possibly reflecting differences in pathogenic mechanisms and diverse clinical manifestations.