Molecular and phenotypic heterogeneity of refractory anemia with ring sideroblasts associated with marked thrombocytosis

Abstract

Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) is a provisional entity within myelodysplastic/myeloproliferative neoplasm (MDS/ MPN), unclassifiable in the 2008 World Health Organiza tion classification. This category includes patients that at the time of initial presentation manifest some diagnostic features (cytopenias and dysplasia) of MDS and others (overproduction of one or more myeloid cell lineages) of MPN. This dual clinical nature limits the distinct clas sification as either MDS or MPN. The diagnostic criteria include peripheral blood (PB; anemia, absence of blasts, platelets  450  10 9 /L) and bone marrow (BM) findings (erythroid dysplasia,  15% of erythroid precursors with RS,  5% blasts, and megakaryocytic hyperplasia with large atypical megakaryocytes) [1,2]. The value of RARS-T as a diagnostic category has remained in question over the years. There is a persistent debate on whether RARS-T is a disease evolving from MDS, is part of the MPN (an essential thrombocythemia (ET) that acquires RS) or is a result of two distinct disorders occurring simultaneously [3]. Data on survival outcomes have also been discordant. RARS-T patients have usually worse outcomes compared to MPN patients and are more likely to develop leukemia although RARS-T patients harboring JAK2 [4,5] or SF3B1 mutations appear to have better survival than wild-type RARS-T patients [5,6]. The presence of DNMT3A and ASXL1 mutations is noted in 17% and 10% of cases and confers an unfavorable prognosis [6,7]. In recent years, molecular analysis has unraveled an overlapping mutational spectrum of RARS-T with MPN or MDS. With the exception of SF3B1 mutations, which have been associated to the RS phenotype in RARS and RARS-T patients [6,8] and linked to the development of erythroid dysplasia, macrocytic anemia, splenomegaly and thrombocytosis in an SF3B1 /2 mouse model [9], the vast majority of mutational events and frequencies have not explained either the MPN or other features of the disease. Indeed mutations in JAK2, MPL, and TET2 are common (60%, 5–20%, and 26%,