Schematic representation of the multistep molecular pathogenesis of RARS-T through sequential acquisition of SF3B1 and JAK2 or MPL mutations. The occurrence of a somatic mutation of SF3B1 causes mitochondrial iron overload, ineffective erythropoiesis, and anemia, typical myelodysplastic features of RARS. The subsequent occurrence of a somatic mutation of JAK2 or MPL involves the emergence of a subclone that carries 2 mutant genes (SF3B1 and JAK2 or MPL) and determines gain of thrombopoietin signaling, proliferation of large atypical megakaryocytes, and thrombocytosis, typical myeloproliferative feature of RARS-T. Adapted from Cazzola et al.⁴⁴