Numerous pathogenicCALRexon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion;CALRDEL) and type 2 (5bp insertion;CALRINS) being the most prevalent. Despite the universal pathobiology of MPN driven by variousCALRmutants, it is unclear why differentCALRmutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched inCALRDELbut not inCALRINSMPN-model cells. The expression ofS100a8could 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-targetingS100a8promoter region inCALRDELcells as compared toCALRINScells, 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 inCALRDELcells. Clinical validation showed significantly enhancedS100A8expression inCALRDEL-mutated MPN patients compared toCALRINS-mutated cases, and thrombocytosis was less prominent in those withS100A8upregulation. This study provides indispensable insights into how differentCALRmutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.