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Numerous pathogenic <i>CALR</i> exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; <i>CALR</i>^DEL) and type 2 (5bp insertion; <i>CALR</i>^INS) being the most prevalent. Despite the universal pathobiology of MPN driven by various <i>CALR</i> mutants, it is unclear why different <i>CALR</i> 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 <i>CALR</i>^DEL but not in <i>CALR</i>^INS MPN-model cells. The expression of <i>S100a8</i> 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 <i>S100a8</i> promoter region in <i>CALR</i>^DEL cells as compared to <i>CALR</i>^INS 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 <i>CALR</i>^DEL cells. Clinical validation showed significantly enhanced <i>S100A8</i> expression in <i>CALR</i>^DEL-mutated MPN patients compared to <i>CALR</i>^INS-mutated cases, and thrombocytosis was less prominent in those with <i>S100A8</i> upregulation. This study provides indispensable insights into how different <i>CALR</i> mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.