Acute myeloid leukemias with ring sideroblasts show a unique molecular signature straddling secondary acute myeloid leukemia and de novo acute myeloid leukemia.

Ring sideroblasts (RS) are a distinct morphological feature present in myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and acute myeloid leukemia (AML). The International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS) defines them as erythroblasts with a minimum of 5 siderotic granules covering at least one third of the circumference of the nucleus. Their presence ≥15% has been associated with mutations in the splicing factor 3B subunit 1 (SF3B1) in 64-83% of patients with refractory anemia with ring sideroblasts (RARS), 57-76% of patients with refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) and in 90% of RARS with thrombocytosis (RARS-T). Recently, the 2016 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemias has recognized the biological importance of SF3B1mut and the correlation with RS, classifying all MDS without excess blasts or 5q deletion into a category of their own. Mutations in SF3B1 are so frequently associated with RS that the threshold at which MDS may be classified as bearing RS has been lowered from the classical 15% to 5% if SF3B1 mutations are demonstrated. Although the impact of SF3B1 mutations was initially associated with better outcomes in MDS, this can be explained through a higher incidence in low-grade MDS and due to the lack of prognostic significance carried by the mutation itself. Recent studies have shown the incidence of SF3B1 in de novo AML is low. However the significance of RS and SF3B1mut in AML had not been assessed in a larger cohort. In an attempt to analyze whether RS could differentiate a subgroup of AML with different biological characteristics, we herein present the biological and clinical associations of RS and SF3B1 mutations in patients with AML (n=1857). From a total of 1857 AML patients (excluding those with cytogenetically defined entities according to WHO), bone marrow assessment revealed 473 (25%) with RS ≥1%, of which 290 (16% of all 1857 patients) had RS ≥5%, and 183 (10% of all 1857 patients) had ≥15% RS, indicating a lower incidence of RS in comparison to cohorts of MDS patients described in the literature (57% of cases showing RS ≥1%). This incidence was, however, significantly higher to that recently reported in AML patients (5%). It must be acknowledged, however, that especially in those cases with lower RS counts, other causes of RS, like alcohol consumption or drug toxicity, cannot be excluded. Next-generation sequencing (NGS) for a panmyeloid panel, gene scan and quantitative polymerase chain reaction (PCR) were performed in a subcohort of 340/473 patients (due to sample availability) for the detection of