Myelodysplastic syndromes, or MDS, are disorders affecting the bone marrow’s ability to produce sufficient healthy blood cells. This condition arises from a malfunction in blood stem cells, which are the building blocks for all blood cells. Instead of maturing properly, these cells can be defective, leading to shortages of red blood cells, white blood cells, and platelets. This results in ineffective hematopoiesis, where the bone marrow is active but fails to deliver functional cells.
Within this broad category, a specific subtype is defined by the presence of “ringed sideroblasts.” These are developing red blood cells in the bone marrow that exhibit a telling abnormality: an accumulation of iron within their mitochondria. This buildup creates a distinctive ring-like pattern around the cell’s nucleus. This subtype, known as MDS with ringed sideroblasts (MDS-RS), represents a unique diagnostic and therapeutic category within the MDS family.
The Cause of Ringed Sideroblasts
The formation of healthy red blood cells, a process called erythropoiesis, is a complex function of the bone marrow. A central element of this process is incorporating iron into heme, a component of hemoglobin that transports oxygen. This task is carried out within the mitochondria. In a healthy cell, iron is efficiently integrated into the heme synthesis pathway.
In MDS-RS, this process is disrupted. The defining characteristic is the abnormal accumulation of iron within the mitochondria of erythroblasts, the precursors to mature red blood cells. Instead of being properly used, the iron builds up and becomes sequestered. This iron overload forms the characteristic ring that is visible under a microscope when the cells are treated with a special iron stain.
The primary driver behind this iron mismanagement in the vast majority of MDS-RS cases is a somatic mutation in a specific gene called SF3B1. This gene provides instructions for a protein that is part of the spliceosome, machinery responsible for RNA splicing. RNA splicing is a process that edits the genetic message from a gene before it is used to build a protein. The mutation in SF3B1 causes this editing process to go awry.
This faulty splicing directly impacts the production of proteins for mitochondrial function and iron metabolism. Research has identified that the missplicing of genes like ABCB7 and TMEM14C, which code for mitochondrial transporter proteins, is a direct consequence of the SF3B1 mutation. The resulting defective proteins impair the cell’s ability to handle iron, leading to its buildup in the mitochondria.
Signs, Symptoms, and Diagnosis
The clinical manifestations of MDS-RS are tied to the bone marrow’s failure to produce enough healthy red blood cells. The most common consequence is anemia, a deficiency of red blood cells or hemoglobin. This shortage impairs the blood’s ability to carry adequate oxygen, leading to persistent fatigue, weakness, shortness of breath during physical activity, and paleness of the skin.
Other signs can include dizziness, headaches, and increased susceptibility to infections if white blood cell counts are also low, or easy bruising if platelet counts are affected. The initial suspicion of MDS-RS often arises from a routine complete blood count (CBC), which can reveal low hemoglobin and other abnormalities. These findings typically prompt further investigation to determine the underlying cause of the cytopenias, or low blood cell counts.
A definitive diagnosis requires a bone marrow aspiration and biopsy. During this procedure, a small sample of bone marrow fluid and tissue is removed, usually from the back of the hip bone. This sample is then sent to a laboratory for analysis by a pathologist. A key step is the application of a Prussian blue stain to the marrow sample.
This stain makes iron deposits visible as blue granules, allowing the pathologist to identify the characteristic ringed sideroblasts. According to World Health Organization (WHO) criteria, a diagnosis of MDS-RS can be made if at least 15% of red blood cell precursors are ringed sideroblasts. If a mutation in the SF3B1 gene is detected, the threshold is lowered to 5%.
Current Treatment Strategies
The management of MDS-RS is tailored to the patient, with the goals of alleviating symptoms, reducing the need for blood transfusions, and improving quality of life. The initial approach often involves supportive care to manage anemia. This includes red blood cell transfusions to boost hemoglobin levels and relieve symptoms like fatigue. Frequent transfusions can lead to iron overload, so iron chelation therapy may be initiated to remove excess iron.
A significant advancement is the targeted therapy luspatercept, which is designed to address the ineffective erythropoiesis in this disease. Luspatercept is an erythroid maturation agent that helps precursor cells to mature more effectively. Clinical trials have shown that luspatercept can reduce transfusion dependence in patients with lower-risk MDS-RS. It is administered as a subcutaneous injection every three weeks.
Beyond luspatercept, other medications may be considered. Erythropoiesis-Stimulating Agents (ESAs) are drugs that mimic a natural hormone to encourage the bone marrow to produce more red blood cells. They are often used in patients who have not responded to other therapies. Lenalidomide may also be used, although its role in MDS-RS is more specific.
For a select group of patients who are younger and in good overall health, an allogeneic stem cell transplant offers the only potential cure for MDS. This procedure involves replacing the patient’s diseased bone marrow with healthy stem cells from a matched donor. Due to the significant risks and potential complications, this option is reserved for a small subset of individuals with higher-risk disease.
Prognosis and Long-Term Outlook
The long-term outlook for individuals with MDS-RS is more favorable compared to other forms of MDS. This is particularly true for patients whose disease is driven by the SF3B1 mutation. The presence of this genetic marker is associated with a slower-progressing clinical course, which translates to a lower risk of the disease transforming into acute myeloid leukemia (AML).
Studies show that patients with SF3B1-mutated MDS have better overall survival rates compared to those with other subtypes of MDS. The median survival for patients with MDS-RS can be several years, with one study noting a median overall survival of 6.6 years. However, the prognosis can be influenced by other factors, such as the presence of additional genetic mutations or the degree of dysplasia in other blood cell lineages.
Given the chronic nature of the condition, long-term management is focused on controlling symptoms and maintaining a good quality of life. This involves regular monitoring of blood counts and ongoing communication with a hematologist to adjust treatment strategies. Follow-up appointments are a standard part of care to assess the effectiveness of ongoing therapies.
The goal is to treat MDS-RS as a manageable chronic illness. With targeted therapies like luspatercept and a better understanding of the disease’s genetic basis, many patients can expect to live for many years. Care remains personalized, ensuring treatment decisions align with the patient’s overall health and goals.