Mutations in components of the erythropoietin (EPO) and thrombopoietin (TPO) signaling pathways, specifically activating mutations in JAK2, CALR, or MPL, can drive aberrant HSC proliferation and clonal expansion and can eventually lead to the development of myeloproliferative neoplasms (MPNs) or MDS/MPN overlap syndromes. The gene discussed is CALR; the disease is myelodysplastic syndrome.