What causes ringed sideroblasts in Myelodysplastic Syndromes (MDS)?

Ringed Sideroblasts in Myelodysplastic Syndromes: Molecular Pathogenesis

Ringed sideroblasts in MDS are primarily caused by mutations in the SF3B1 gene, which encodes a core component of the RNA splicing machinery. SF3B1 mutations are present in 15-30% of MDS cases and are strongly associated with the presence of ring sideroblasts, particularly in MDS subtypes classified as MDS-RS (MDS with ring sideroblasts). 1

Molecular Basis of Ring Sideroblast Formation

SF3B1 Mutations and Splicing Defects

• SF3B1 is a core component of the spliceosome complex responsible for pre-mRNA splicing
• Mutations in SF3B1 lead to aberrant splicing of various genes involved in:
  • Heme biosynthesis
  • Mitochondrial iron metabolism
  • Erythroid differentiation

Pathophysiological Mechanism

1. Mitochondrial Iron Accumulation: SF3B1 mutations cause dysregulated iron metabolism in erythroid precursors, leading to excessive iron accumulation in mitochondria
2. Aberrant Heme Synthesis: The splicing defects affect genes involved in heme biosynthesis, resulting in impaired heme production
3. Activation of EIF2AK1 Pathway: Recent research shows SF3B1 mutations activate the EIF2AK1 pathway in response to heme deficiency 2

Diagnostic Classification

Ring sideroblasts are a key morphological feature in the WHO 2016 classification of MDS:

• MDS-RS-SLD: MDS with ring sideroblasts with single lineage dysplasia (≥15% ring sideroblasts or ≥5% if SF3B1 mutation is present) 1
• MDS-RS-MLD: MDS with ring sideroblasts with multilineage dysplasia 1
• MDS/MPN-RS-T: MDS/MPN with ring sideroblasts and thrombocytosis (≥450 × 10^9/L platelets) 3

Genetic Landscape

Mutation Frequencies in MDS-RS

• SF3B1: 80-90% of MDS-RS cases 1, 3
• Other less common mutations in MDS-RS include:
  • TET2: 15-25% 1
  • DNMT3A: 10% 1
  • ASXL1: 10-20% 1
  • JAK2 V617F: Common in MDS/MPN-RS-T (approximately 50%) 3

Contrast with Non-SF3B1 Ring Sideroblasts

In AML with ring sideroblasts, the genetic profile differs significantly:

• SF3B1 mutations are uncommon (only 8%)
• More frequent mutations in TP53 (37%), DNMT3A (26%), and RUNX1 (25%) 4

Clinical Significance

• MDS-RS generally has a favorable prognosis compared to other MDS subtypes, especially when SF3B1 mutation is isolated 1
• Patients with MDS-RS typically have lower risk of progression to AML 3
• The main clinical challenge is transfusion-dependent anemia and subsequent iron overload 3
• MDS/MPN-RS-T has better outcomes than MDS-RS-SLD but worse than essential thrombocythemia 3, 5

Therapeutic Implications

The understanding of SF3B1's role in ring sideroblast formation has led to targeted therapeutic approaches:

• Luspatercept: Recently approved for managing anemia in patients with MDS-RS 3
• EIF2AK1 inhibitors: Emerging as potential therapeutic targets to rescue red blood cell production in SF3B1-mutant MDS-RS 2

Key Pitfalls in Diagnosis and Management

1. Not all ring sideroblasts in myeloid neoplasms are associated with SF3B1 mutations
2. The presence of ring sideroblasts alone is insufficient for diagnosis; comprehensive evaluation including cytogenetics and molecular testing is essential
3. SF3B1 mutations may confer a relatively favorable prognosis in MDS-RS but require monitoring for transfusion dependency and iron overload

Understanding the molecular basis of ring sideroblast formation in MDS has significant implications for diagnosis, classification, risk stratification, and emerging targeted therapies.