Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts

Abstract

Myeloid neoplasms with ring sideroblasts are currently categorized within the myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in the World Health Organization classification. Recent findings have identified that the presence of ring sideroblasts in these disorders has a unique molecular basis, i.e., the somatic mutation of SF3B1, a gene encoding a splicing factor. Mutations of SF3B1 occur in up to 90% of patients with refractory anaemia with unilineage dysplasia (RARS) and 70% of those with refractory cytopenia with multilineage dysplasia and ring sideroblasts or RARS associated with marked thrombocytosis. Experimental evidence has shown that mutant SF3B1 results in the abnormal splicing of several genes, primarily due to misrecognition of 3' splice sites. The resulting aberrant mRNAs undergo nonsense-mediated mRNA decay (NMD), resulting in haploinsufficiency of canonical transcripts and protein expression. In addition, it is also possible that NMD-insensitive aberrant transcripts are translated into proteins with altered function. Patients with MDS carrying the SF3B1 mutation show a homogeneous disease phenotype characterized by isolated erythroid dysplasia and mild dysplasia in granulocytic or megakaryocytic lineages, supporting the notion that the SF3B1 mutation identifies a distinct entity within MDS. The available evidence suggests that these findings may have relevant impact on the diagnosis, classification and management of patients with these neoplasms.

Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic syndromes

“…SF3B1 mutations in MDS are associated with mitochondrial iron sequestration and ineffective erythropoiesis. 24 EZH2 and SF3B1 comutations are associated with more severe anemia and transfusion dependence in MDS-RS. 22 To define the basis by which these mutations perturb erythropoiesis, we differentiated CD34 1 CD43 1 HPCs from subclonal iPSCs to CD71 1 CD235a 1 erythroid cells.…”

Sideroblastic anemia associated with multisystem mitochondrial disorders

“…Variants of this condition include refractory cytopenia with multilineage dysplasia and ring sideroblasts and RARS, associated with marked thrombocytosis (combined myelodysplastic and myeloproliferative disorder). Somatic mutations in SF3B1 are found in ≥80% of patients, sometimes in combination with mutations in other genes, including JAK2V617F, ASXL1, DNMT3A, SETBP1 , and TET2 . Congenital SA is associated with mutations in nuclear genes involved in heme biosynthesis ( ALAS2 and SLC25A38 ), iron‐sulfur‐cluster biogenesis/transport ( ABCB7 and GLRX5 ), thiamine‐transport protein ( SLC19A1 ), structural subunits of the respiratory chain complex ( NDUFB11 ), and mitochondrial protein synthesis and chaperones ( PUS1, YARS2, LARS2 , and HSPA9 ) or with mutations in mitochondrial DNA ( MTATP6 , or large mtDNA deletions) involved in mitochondrial biogenesis …”

“…Somatic mutations in SF3B1 are found in ≥80% of patients, sometimes in combination with mutations in other genes, including JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2. 2,3 Congenital SA is associated with mutations in nuclear genes involved in heme biosynthesis (ALAS2 and SLC25A38), iron-sulfurcluster biogenesis/transport (ABCB7 and GLRX5), thiamine-transport protein (SLC19A1), structural subunits of the respiratory chain complex (NDUFB11), and mitochondrial protein synthesis and chaperones (PUS1, YARS2, LARS2, and HSPA9) or with mutations in mitochondrial DNA (MTATP6, or large mtDNA deletions) involved in mitochondrial biogenesis. [4][5][6][7][8][9][10][11] Although the association between hematological pathology and mitochondrial disorders is generally accepted, collaboration between hematologists and mitochondrial researchers is not common.…”

New developments in the understanding and diagnosis of myelodysplastic syndromes with ring sideroblasts

“…Moreover, MDS patients carrying SF3B1 mutations present a fairly homogeneous disease phenotype often characterized by isolated erythroid dysplasia, significant erythroid dysplasia, and high proportion of RS. Even more importantly, these patients present significantly better survival and lower risk of progression to AML 11, 12. Together, these data supported a significant change in the revised WHO classification of MDS in 2016, which established that, in the presence of a SF3B1 mutation, a diagnosis of MDS-RS may be defined with RS in as few as 5% of nucleated erythroid cells, with the former threshold of 15% RS reserved for cases lacking a demonstrable SF3B1 mutation 13 .…”