Mutation-Driven S100A8 Overexpression Confers Aberrant Phenotypes in Type 1 CALR -Mutated MPN.

Numerous pathogenic exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; ) and type 2 (5bp insertion; ) being the most prevalent. Despite the universal pathobiology of MPN driven by various mutants, it is unclear why different mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in but not in MPN-model cells. The expression of could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting promoter region in cells as compared to cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in cells. Clinical validation showed significantly enhanced expression in -mutated MPN patients compared to -mutated cases, and thrombocytosis was less prominent in those with upregulation. This study provides indispensable insights into how different mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.