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

Abstract

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).1-5 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.6 Mutations in SF3B1 are so frequently associated with RS 7 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.6 Although the impact of SF3B1 mutations was initially associated with better outcomes in MDS, 1,7 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.4 Recent studies have shown the incidence of SF3B1 in de novo AML is low.7,8 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%).9 This incidence was, however, significantly higher to that recently reported in AML patients (5%).7 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 © Ferrata Storti Foundation

Ring sideroblasts in AML are associated with adverse risk characteristics and have a distinct gene expression pattern

“…Although RS are generally regarded as a specific feature of certain MDS subtypes, the reported incidence of 25% indicates that RS is -log10 -value p also a rather common finding in AML. 18 In contrast to reports on MDS-RS subtypes, mutations in spliceosome gene SF3B1 were rarely observed in our RS-AML cohort. The paucity of this mutation in RS-AML might be explained by the low tendency toward AML transformation from MDS subtypes with SF3B1 mutations.…”

“…These results are in agreement with a previous study using a restricted gene panel to analyze the RS phenotype in patients with AML. 18 The high incidence of poor-risk cytogenetic aberrancies, including chromothripsis, probably reflects the high frequency of TP53 mutations. 30 In the present study, we have primarily included patients with de novo AML reflecting the lack of a clinical relevant history of antecedent MDS.…”

“…33 The presence of RS in our AML cohort is not restricted to a specific ontogenic subtype, 34 indicating that RS in AML arise from a common mechanism that goes beyond disease ontogeny. Also, it has been reported that the presence of RS on its own is not predictive for OS in patients with AML, 18 suggesting that RS-AML is not a distinct disease entity. However, we observed several differences in megakaryocytic and erythroid differentiation gene expression that are specific for RS-AML compared with non-RS-AML, suggesting a role for the MEP cell.…”

“…[8][9][10][11][12] Moreover, RS can also be present in a subset of patients with acute myeloid leukemia (AML), whereas SF3B1 mutations are infrequent in this disease. 10,18,19 In addition to SF3B1, the only other correlation between a gene defect and the RS phenotype was described for PRPF8, for which mutations are reported in ;3% of myeloid neoplasms, including MDS, MDS/MPN, and (s)AML. 20 In the present study, we determined the prevalence of RS in various ontogenic AML subtypes and the association of the RS phenotype in AML with adverse risk characteristics.…”

Acquired Sideroblastic Anemia: An exploratory Comparative Statistical Analysis Between Clonal and Non-clonal cases

“…We had a single case of a male patient diagnosed at a relatively younger age (37 years old) and considered the youngest among all groups of myeloid neoplasms with RS in our cohort. Martin-Cabrera et al 13 recently reported that AML with RS shows a unique molecular signature straddling secondary AML and de novo AML.…”