Myelodysplastic Syndrome

By SWA

Myelodysplastic Syndrome (MDS) / Myelodysplastic Neoplasms: A Comprehensive Medical Overview

Introduction

Myelodysplastic syndromes (MDS), now referred to by the World Health Organization (WHO) 2022 classification as myelodysplastic neoplasms, are a group of clonal hematologic malignancies affecting the bone marrow and blood. In MDS, immature blood cells (hematopoietic stem cells) in the bone marrow do not mature properly and fail to produce enough healthy red cells, white cells, or platelets. This ineffective hematopoiesis leads to blood cytopenias, marrow dysplasia, and in some cases, progression to acute myeloid leukemia (AML).

Understanding the Basics: Normal vs. Abnormal Blood Formation

In a healthy individual, the bone marrow continuously produces:

  • Red blood cells (carry oxygen)

  • White blood cells (fight infection)

  • Platelets (help blood clot)

This production process begins with blood stem cells, which mature through tightly controlled pathways. In MDS, genetic and epigenetic changes disrupt this process, leading to immature or dysfunctional blood cells that may die prematurely or fail to function properly.

How Serious Is Myelodysplasia?

MDS ranges from mild, slowly progressing forms to aggressive subtypes that can evolve into acute myeloid leukemia (AML). This progression, known as "leukemic transformation", can occur over months to years, depending on the risk category.

The disease's seriousness depends on:

  • Type and number of cytopenias

  • Cytogenetic abnormalities

  • Percentage of blasts in the bone marrow

  • Presence of high-risk mutations

Signs, Symptoms, and Red Flags

MDS symptoms are typically due to bone marrow failure, resulting in:

Red Flags and Common Symptoms

SymptomCause
Fatigue, weakness, pallor    Anemia (low red cells)
Shortness of breath, lightheadedness, headache    Anemia
Frequent infections    Neutropenia (low white cells)
Bruising and bleeding    Thrombocytopenia (low platelets)
Mouth sores, sore throat, or sinus infections    Neutropenia
Bone or joint pain    Marrow expansion or infiltration (less common but possible in MDS)

    Immunophenotyping. ...
    Genetic profiling using Next Generation Sequencing (NGS) of DNA.

Is Myelodysplasia Painful?

While MDS itself does not always cause pain, bone or joint pain can occur in some patients—especially if the disease progresses or becomes inflammatory. This pain is typically felt in:

  • Long bones (arms, legs)

  • Ribs

  • Sternum (breastbone)

  • Large joints (hips, shoulders)

Pain may precede transformation to more aggressive disease.

Diagnosis of Myelodysplastic Neoplasms

Diagnostic Criteria (ESMO/WHO Guidelines)

MDS diagnosis is based on a combination of:

  • Persistent cytopenias in peripheral blood

  • Dysplasia in ≥10% of cells in one or more myeloid lineages

  • Hypercellular or hypocellular bone marrow with abnormal maturation

  • Blasts <20% (if ≥20%, it's considered AML)

  • Cytogenetic or molecular abnormalities

Diagnostic Tests for MDS

TestPurpose
Complete Blood Count (CBC)Detects anemia, neutropenia, and thrombocytopenia
Peripheral Blood SmearIdentifies dysplastic features (e.g., abnormal red cell shapes, hypo- or hypersegmented neutrophils)
Bone Marrow Aspiration and BiopsyEssential to assess cellularity, dysplasia, and blast percentage
Cytogenetic Analysis (Karyotyping, FISH)Identifies chromosomal abnormalities (e.g., del(5q), -7, +8)
Molecular Testing / Next-Generation Sequencing (NGS)Detects mutations in key genes (e.g., SF3B1, TET2, ASXL1, RUNX1)
Immunophenotyping (Flow Cytometry)Evaluates cell surface markers, especially if transformation to AML is suspected

Genetic and Epigenetic Pathogenesis

MDS arises due to acquired somatic mutations and epigenetic alterations in hematopoietic stem cells, leading to abnormal blood cell development.

Key Pathogenic Mechanisms:

1. Genetic Mutations

Commonly mutated genes in MDS include:

  • RNA splicing: SF3B1, SRSF2

  • DNA methylation: TET2, DNMT3A

  • Chromatin modification: ASXL1

  • Transcription factors: RUNX1

  • Signaling pathways: JAK2, NRAS

2. Cytogenetic Abnormalities

Frequent chromosomal changes include:

  • del(5q): Often associated with a better prognosis

  • Monosomy 7 / del(7q): High-risk

  • Complex karyotypes: Very poor prognosis

3. Epigenetic Changes

Altered DNA methylation and histone modification lead to:

  • Silencing of tumor suppressor genes

  • Dysregulation of cell growth and differentiation

Classification of MDS

WHO 2022 Classification Highlights

  • Introduced the term "myelodysplastic neoplasms"

  • Includes genetic-defined entities (e.g., MDS with mutated SF3B1)

  • Categories based on blast count, genetic alterations, and cell lineage involvement

IPSS-R (Revised International Prognostic Scoring System)

Stratifies patients into very low to very high-risk groups based on:

  • Cytopenias

  • Cytogenetics

  • Bone marrow blast percentage

This system is crucial for determining prognosis and therapy.

Treatment Options for MDS

1. Supportive Care

  • Blood transfusions (for anemia)

  • Platelet transfusions

  • Iron chelation (for transfusion-dependent iron overload)

  • Growth factors: Erythropoietin (EPO), G-CSF

  • Antibiotics for infections

2. Disease-Modifying Therapies

  • Lenalidomide: Especially effective in del(5q) MDS

  • Hypomethylating agents:

    • Azacitidine and decitabine improve survival and delay AML progression

  • Luspatercept: For MDS with ring sideroblasts and transfusion dependency

  • Immunosuppressive therapy: In select patients (e.g., younger, hypocellular marrow)

3. Curative Therapy: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

  • Only curative treatment for MDS

  • Suitable for fit patients, especially under age 65 with high-risk MDS

     

 Prognosis and Transformation to AML

The natural history of MDS is variable:

  • Some patients live for years with mild disease

  • Others progress to AML—especially those with high-risk cytogenetics or multiple gene mutations

Transformation to AML is typically associated with:

  • Increase in bone marrow blasts (>20%)

  • Worsening cytopenias

  • Acquisition of additional mutations

Conclusion

Myelodysplastic neoplasms represent a complex, heterogeneous group of bone marrow cancers characterized by ineffective hematopoiesis, genetic instability, and risk of leukemic transformation. Diagnosis requires a multimodal approach, including morphology, cytogenetics, and molecular studies. Treatment ranges from supportive care to curative stem cell transplantation, depending on disease severity, risk category, and patient factors.

References and Resources


© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742


Comments

Post a Comment

Popular posts from this blog

Schnitzler Syndrome: A Rare Autoinflammatory Disorder

By SWA
Schnitzler syndrome is a rare, chronic autoinflammatory disease characterized by chronic urticaria (hives), recurrent fever, joint pain, and monoclonal gammopathy (abnormal proteins in the blood). First described by Dr. Liliane Schnitzler in 1972 , this condition is often misdiagnosed, leading to years of untreated symptoms before a correct diagnosis is made. The case report, " A 58-Year-Old Woman With Urticaria, Fever, and Joint Pain " , describes a case that closely aligns with my own experience with this challenging disorder. Key Features of Schnitzler Syndrome Schnitzler syndrome presents with a characteristic set of symptoms, though not all patients experience them in the same way: Chronic Urticaria (Hives) – Persistent, non-itchy or mildly itchy red patches that do not respond to antihistamines. Monoclonal Gammopathy (IgM or IgG type) – Abnormal monoclonal immunoglobulin detected in the blood (most commonly IgM ). Recurrent Fever – Unexplained fever episodes, often...
Read more

Dysferlin Protein: Key Roles, Genetic Locations

By SWA
Image
The purpose of this article is to share and discuss the details of a new discovery, which is highlighted within: CRISPR-Cas9: A Breakthrough Tool to Repair the DYSF Gene The dysferlin protein plays an essential role in maintaining the integrity of muscle cell membranes, particularly in tissues that endure significant mechanical stress, such as skeletal and cardiac muscles . Encoded by the DYSF gene , dysferlin is indispensable for repairing damaged cell membranes after injury caused by muscle contraction or external forces. This article explores the main locations where dysferlin is produced, its role in muscle repair, and supportive nutritional and therapeutic strategies for individuals with dysferlin deficiency, such as those affected by dysferlinopathies (e.g., Limb-Girdle Muscular Dystrophy Type 2B or Miyoshi Myopathy). Currently, there is no definitive answer as to why the severity of dysferlin protein expression or depletion varies. Do pathogens play a role in the methylation o...
Read more

Very Long-Chain Fatty Acids (VLCFAs) X-ALD and Spinal Muscular Atrophy (SMA): Exploring the Connection

By SWA
Update Oct 28th 2024:  A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.27117 Very Long-Chain Fatty Acids (VLCFAs) are a specific type of fatty acid that are broken down in the body by specialized cellular structures called peroxisomes. These organelles play a critical role in maintaining metabolic balance by degrading VLCFAs. When this process is disrupted, VLCFAs accumulate in various tissues, which can lead to serious metabolic and neurological complications. Elevated VLCFA levels are characteristic of several peroxisomal disorders, most notably X-linked Adrenoleukodystrophy (X-ALD) and Zellweger Syndrome. In X-ALD, for example, a genetic defect impairs the peroxisomal breakdown of VLCFAs, resulting in their accumulation in the brain, spinal cord, and adrenal glands. This buildup can cause progressive neurological damag...
Read more