Myelodysplastic Syndromes (MDS) are a group of blood disorders where the bone marrow fails to produce healthy, mature blood cells. This results in low blood counts (cytopenias) because blood cells often die early, a process called ineffective hematopoiesis. MDS disorders are classified into distinct subtypes based on the type of blood cell affected and the specific genetic changes present. Identifying these genetic abnormalities is essential for determining the best treatment plan and understanding the disease’s likely course. The presence of a specific change, known as the 5q deletion, defines one unique subtype of MDS.
Understanding Myelodysplastic Syndromes and the 5q Deletion
MDS is a clonal disorder affecting myeloid stem cells, meaning the disease originates from a single, damaged precursor cell that replicates itself. This results in the production of structurally abnormal blood cells that cannot function correctly. Consequently, the bone marrow becomes crowded with immature cells while the peripheral blood lacks sufficient mature red cells, white cells, and platelets.
The “5q deletion” refers to the loss of genetic material from the long arm (“q” arm) of chromosome 5, specifically spanning bands between 5q31 and 5q33. This genetic change is the single most common chromosomal abnormality found in MDS patients. The World Health Organization (WHO) recognizes Myelodysplastic Syndrome with isolated del(5q) as a distinct entity. This diagnosis is reserved for patients where del(5q) is the sole chromosomal abnormality, or occasionally with only one other non-adverse abnormality.
The deletion includes a “commonly deleted region” (CDR) containing approximately 40 genes necessary for cell growth and differentiation. The loss of these genes causes haploinsufficiency, where having only one copy of the gene is insufficient to produce the necessary protein amount. For example, the affected gene RPS14 is involved in making ribosomal components, and its reduced production impairs red blood cell maturation, contributing to the characteristic anemia.
Signs, Symptoms, and Diagnostic Testing
The physical manifestations of MDS with 5q deletion result primarily from low blood cell counts (cytopenia). The most common symptom is anemia, defined as a low count of red blood cells or hemoglobin. This anemia is typically macrocytic, meaning the red blood cells produced are abnormally large. Patients experience fatigue, shortness of breath, and paleness, which are classic signs of anemia. The severity of the anemia often necessitates regular red blood cell transfusions for support.
A unique feature of the isolated 5q deletion subtype is that patients often have normal or elevated platelet counts and usually do not have a significant lack of white blood cells. The diagnostic process begins with a complete blood count (CBC), which reveals the cytopenias and macrocytic anemia. If MDS is suspected, a bone marrow biopsy is performed to examine the cellular structure and percentage of immature cells, or blasts. The bone marrow in this subtype is typically hypercellular, meaning it contains an increased number of cells, despite the low counts in the peripheral blood.
The diagnosis is confirmed through specialized genetic testing performed on the bone marrow sample. Conventional cytogenetics (karyotyping) is the gold standard for visualizing chromosomes and identifying the deletion on chromosome 5. Fluorescence in situ hybridization (FISH) testing is also routinely used, employing fluorescent probes to quickly detect the specific 5q deletion. The diagnosis of isolated del(5q) is made when the deletion is present and the percentage of blasts in the bone marrow is less than 5%.
Targeted Treatment Approaches
The treatment strategy for Myelodysplastic Syndrome with 5q deletion is focused on achieving transfusion independence, particularly in lower-risk patients. This removes the need for frequent blood transfusions, which improves the patient’s quality of life and reduces risks associated with long-term dependence, such as iron overload.
Lenalidomide, an immunomodulatory drug, is the established first-line treatment for lower-risk patients who have transfusion-dependent anemia and the del(5q) abnormality. Clinical studies have consistently shown that lenalidomide induces durable transfusion independence in a significant proportion of these patients. This strong response is a hallmark of the 5q deletion subtype, as the drug is much less effective in MDS patients without this specific genetic change.
The drug’s targeted effectiveness is rooted in its unique mechanism of action, which involves binding to a protein called cereblon (CRBN). This binding then leads to the degradation of a protein called Casein Kinase 1A1 (CK1α), which is encoded by a gene located in the deleted region of chromosome 5. Because del(5q) cells already have only one copy of the CK1α gene, the drug-induced degradation of the remaining protein copy causes the cancerous cells to die off selectively.
Lenalidomide also works by promoting the degradation of other proteins and by stabilizing the MDM2 protein, which ultimately leads to the breakdown of the tumor suppressor protein p53 in the abnormal cells. This selective targeting allows healthy blood stem cells to proliferate, effectively “resetting” the bone marrow’s production process. While lenalidomide is highly effective, side effects such as low white blood cell counts (neutropenia) and low platelet counts (thrombocytopenia) are common and require close monitoring and dose adjustments.
For patients who do not respond to lenalidomide or have other complicating factors, alternative treatments may be considered. Erythropoiesis-stimulating agents (ESAs) are growth factors that can help boost red blood cell production, though they are often less effective than lenalidomide in this specific subtype. The use of hypomethylating agents or even a stem cell transplant, which is potentially curative, is generally reserved for patients with higher-risk disease or those whose condition progresses.
Clinical Outlook and Disease Monitoring
MDS with isolated del(5q) typically carries a favorable prognosis compared to many other forms of Myelodysplastic Syndrome. The disease course is often indolent, meaning it progresses slowly, especially when the 5q deletion is the only genetic abnormality present.
Prognosis is assessed using risk stratification tools like the Revised International Prognostic Scoring System (IPSS-R). This system evaluates factors including the percentage of blasts in the bone marrow, the number of low blood cell types, and specific cytogenetic abnormalities. The isolated del(5q) usually places patients into lower-risk categories, such as “Very Low” or “Low” risk.
Despite the favorable outlook, there is a risk of the disease progressing to an aggressive form of blood cancer, Acute Myeloid Leukemia (AML). Approximately 20% to 25% of patients with MDS-del(5q) eventually experience this transformation. The risk of AML transformation is significantly higher if the patient has additional cytogenetic abnormalities or specific gene mutations, such as those in TP53.
Long-term management involves regular monitoring to detect any signs of disease progression or new genetic changes. This monitoring includes frequent blood counts, periodic bone marrow examinations, and repeat cytogenetic testing. Recently developed scoring systems, such as the IPSS-del(5q), aim to more accurately identify patients at higher risk of progressing to AML, allowing for alternative treatment planning.