Key Points An increase in the classical monocyte subset to >94% of total monocytes discriminates CMML from other monocytoses with high specificity. This characteristic increase in classical monocytes disappears in CMML patients who respond to hypomethylating agents.

Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in theSF3B1splicing factor gene. Patients with MDS withSF3B1mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternativeERFEtranscript in patients with MDS with theSF3B1mutation. Induction of thisERFEtranscript in primarySF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with anSF3B1gene mutation than in patients withSF3B1wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients withSF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variantERFEtranscript that was restricted toSF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.