MDS 5q Deletion: Pathophysiology, Prognosis, and Care

Myelodysplastic syndrome (MDS) with isolated deletion of the long arm of chromosome 5, known as MDS 5q-, is a distinct subtype of MDS. It primarily affects older adults and is characterized by anemia, dysplastic bone marrow features, and an increased risk of progression to acute myeloid leukemia (AML). Despite being a form of MDS, it generally has a more favorable prognosis than other subtypes.

Genetic Basis Of The Deletion

MDS 5q- is defined by the deletion of a segment on the long arm of chromosome 5 (5q), disrupting multiple genes involved in hematopoiesis. While the deletion varies in size among patients, it consistently affects a critical region essential for bone marrow function. Key genes within this region include RPS14, which plays a role in ribosomal biogenesis, and CSNK1A1, a regulator of p53 degradation. Their loss contributes to erythroid dysplasia and ineffective hematopoiesis.

Haploinsufficiency of RPS14 leads to defective ribosomal processing, triggering a p53-mediated stress response that impairs erythroid differentiation. This mechanism resembles the pathophysiology of Diamond-Blackfan anemia, another disorder linked to ribosomal dysfunction. The selective impact on erythroid progenitors explains why anemia is the predominant feature in MDS 5q-, while other blood cell lines remain relatively intact.

Additionally, the deletion affects genes involved in cytokine signaling, such as HSPA9 and MIR145/MIR146A. The loss of these microRNAs leads to increased expression of pro-inflammatory cytokines and disrupted hematopoietic stem cell function, contributing to broader bone marrow abnormalities.

Pathophysiology

The 5q deletion impairs hematopoietic stem and progenitor cells, particularly within the erythroid lineage. A key feature of this process is heightened p53 activity, which induces apoptosis in erythroid progenitors, causing ineffective erythropoiesis and macrocytic anemia.

Bone marrow biopsies consistently reveal dysplastic megakaryocytes with hypolobulated nuclei, arising from disrupted differentiation pathways. These atypical megakaryocytes persist despite suppressed erythroid precursors, highlighting lineage-specific vulnerabilities. While erythropoiesis is severely impaired, myeloid and platelet lineages are often relatively preserved.

The loss of CSNK1A1 disrupts p53 degradation, leading to its accumulation in hematopoietic progenitor cells. This exaggerated p53 response not only promotes apoptosis but also alters stem cell self-renewal, contributing to bone marrow failure. Additionally, defects in cell cycle regulation impair progenitor cell proliferation, resulting in hypocellular marrow with an expansion of dysplastic elements.

Diagnostic Methods

Diagnosing MDS 5q- requires hematologic evaluation, bone marrow analysis, and cytogenetic testing to confirm the 5q deletion. Patients typically present with macrocytic anemia, often with a normal or slightly reduced white blood cell count and preserved or mildly elevated platelet levels. A complete blood count (CBC) reveals anemia with an increased mean corpuscular volume (MCV) and low reticulocyte counts, reflecting ineffective erythropoiesis.

Bone marrow aspiration and biopsy reveal hypercellular or normocellular marrow with prominent erythroid dysplasia. A hallmark feature is small, hypolobulated megakaryocytes, which can be identified using immunohistochemical markers like CD61 or CD42b.

Cytogenetic testing confirms the diagnosis, with conventional G-banding karyotyping being the gold standard. Fluorescence in situ hybridization (FISH) offers enhanced sensitivity, while single nucleotide polymorphism (SNP) arrays and next-generation sequencing (NGS) provide higher-resolution analysis, detecting submicroscopic deletions and coexisting mutations that may influence prognosis and treatment response.

Clinical Manifestations

MDS 5q- typically presents with macrocytic anemia, leading to fatigue, pallor, and reduced exercise tolerance. Unlike other MDS subtypes, it is not commonly associated with severe leukopenia or thrombocytopenia. In some cases, platelet counts may be elevated due to functionally active dysplastic megakaryocytes.

Despite bone marrow failure, patients rarely experience significant bleeding or recurrent infections, as neutrophil function remains largely intact. Ineffective hematopoiesis results in increased erythropoietin levels, though endogenous stimulation is insufficient to correct anemia. Many individuals require transfusion support over time, particularly if additional cytogenetic abnormalities emerge.

Prognostic Considerations

MDS 5q- generally has a more favorable prognosis than other MDS subtypes, with lower rates of transformation to AML. The Revised International Prognostic Scoring System (IPSS-R) often classifies these patients as lower risk, with survival measured in years rather than months. However, additional genetic mutations, patient age, and comorbidities influence disease trajectory. The presence of secondary cytogenetic abnormalities, such as TP53 mutations, is associated with a more aggressive course and diminished response to therapy.

Transfusion dependency and bone marrow characteristics provide further prognostic insight. Patients who remain transfusion-independent tend to have better outcomes, as chronic transfusions contribute to iron overload and organ dysfunction. An increase in marrow blasts may signal progression toward AML, necessitating close monitoring with repeated biopsies and molecular testing.

Therapeutic Approaches

Treatment aims to alleviate anemia, reduce transfusion dependence, and prevent disease progression. The approach depends on patient-specific factors, including age, comorbidities, and cytogenetic findings. Supportive care, such as transfusions and iron chelation therapy, plays a key role in symptom management.

Lenalidomide Therapy

Lenalidomide is the primary treatment for transfusion-dependent MDS 5q- patients, selectively targeting 5q- clone cells while preserving normal hematopoiesis. Clinical trials show that approximately 67% of patients achieve transfusion independence, with many also experiencing cytogenetic remission. The drug modulates CSNK1A1 degradation, promoting apoptosis in malignant cells while supporting erythroid recovery. However, lenalidomide can cause myelosuppression, requiring careful dose adjustments and monitoring.

Erythropoiesis-Stimulating Agents (ESAs) and Supportive Care

For patients ineligible for lenalidomide or with milder anemia, erythropoiesis-stimulating agents (ESAs), such as recombinant erythropoietin, may enhance red blood cell production. ESAs are most effective in those with low endogenous erythropoietin levels but are generally less effective in MDS 5q- due to ribosomal dysfunction. In refractory cases, red blood cell transfusions provide symptomatic relief, though long-term dependence necessitates iron chelation therapy.

Allogeneic Stem Cell Transplantation and Emerging Therapies

For younger patients or those with high-risk mutations, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option. However, due to the typically indolent nature of MDS 5q-, HSCT is rarely pursued unless disease progression is evident. The risks of graft-versus-host disease and transplant-related mortality must be carefully weighed.

Ongoing research into targeted therapies, such as agents modulating p53 activity, may expand treatment options for patients unresponsive to conventional approaches. Clinical trials continue to explore novel drug combinations and precision medicine strategies to improve outcomes while minimizing toxicity.