Understanding Myelodysplastic Syndromes (MDS): A Patient's Guide to the Disease Mechanisms and Classifications

Table of Contents

• Introduction: What Are Myelodysplastic Syndromes?
• Definitions and Diagnostic Criteria
• How MDS Develops: The Pathophysiology
• Key Mutation-Driver Genes in MDS
• Pathophysiology of Specific MDS Subtypes
• Progression to Leukemia (Leukemic Transformation)
• Inherited (Germline) Predisposition
• What This Means for Patients: Clinical Implications
• Understanding the Limitations
• Source Information

Introduction: What Are Myelodysplastic Syndromes?

Myelodysplastic syndromes, or MDS, are a group of complex blood cancers. The term "myelodysplasia" comes from Greek words meaning "abnormal formation," which perfectly describes what happens in the bone marrow of patients with this condition. Historically, in 1982, an international group of experts used this term to describe the abnormal appearance of blood-forming cells seen in pre-leukemic conditions.

Our understanding of MDS has evolved significantly, especially since 2001 when the World Health Organization (WHO) began creating a classification system that combines how the cells look under a microscope with genetic information. This system has been revised several times, most recently in 2016, to help doctors make better treatment decisions. Furthermore, scoring systems like the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) were developed to help predict patient outcomes.

With modern genetic sequencing technology, we now know that most MDS patients have acquired (somatic) gene mutations that are closely linked to how their disease will behave. MDS occurs mainly in older adults, with a median age of about 70 years at diagnosis. The overall incidence is estimated at 4 to 5 new cases per 100,000 people per year. However, the true incidence is likely higher due to underreporting, and it may be as high as 75 cases per 100,000 among people over the age of 70.

Definitions and Diagnostic Criteria

MDS is defined as a type of blood cancer (myeloid neoplasm) characterized by several key features. It involves the clonal proliferation of blood stem cells, meaning a single, genetically abnormal cell multiplies and crowds out healthy cells. This leads to recurrent genetic abnormalities, visible cell abnormalities (morphologic dysplasia), inefficient blood production (ineffective hematopoiesis), low blood cell counts (peripheral-blood cytopenia), and a high risk of evolving into acute myeloid leukemia (AML).

MDS has traditionally been classified into two categories:

• Primary MDS: Occurs without any known previous history of chemotherapy or radiotherapy.
• Therapy-related MDS: Occurs as a late complication of previous cancer treatment. This type is now included in the WHO category of therapy-related myeloid neoplasms.

There are also overlap conditions, called myelodysplastic-myeloproliferative neoplasms, which have features of both MDS and diseases where blood cells overproliferate. Importantly, there are precursor conditions that can develop into full MDS:

• Clonal Hematopoiesis of Indeterminate Potential (CHIP): A person has normal blood cell counts but carries a somatic mutation (with a variant allele frequency of at least 2%) in a gene commonly linked to blood cancers.
• Clonal Cytopenia of Undetermined Significance (CCUS): A person has unexplained low blood cell counts (cytopenia) and a somatic mutation (with a variant allele frequency of at least 20%) but does not yet meet the full WHO criteria for an MDS diagnosis.

The core diagnostic criteria for MDS are persistent low blood cell counts in one or more cell lines and morphologic dysplasia (at least 10% of cells looking abnormal) in one or more bone marrow cell lines. The specific subtypes of MDS are then determined by the number of dysplastic cell lines, the presence of ring sideroblasts, the percentage of blast cells (immature cells), and the type of chromosomal abnormality found.

How MDS Develops: The Pathophysiology

The development of MDS is a process driven by the growth and spread of a clone of cells that have acquired genetic mutations. These mutations, called "driver mutations," give the abnormal cells a survival and growth advantage over healthy cells. The process can be broken down into four phases.

Phase 1: Initial Clone Growth. An initiating driver mutation occurs in a single hematopoietic stem cell (a blood-forming stem cell). This generates a local clone of mutant stem cells and abnormal blood progenitor cells.

Phase 2: CHIP (Clonal Hematopoiesis of Indeterminate Potential). Mutant stem cells migrate through the blood and settle in different areas of the bone marrow, forming more local clones. When these mutant cells account for at least 4% of all bone marrow cells (corresponding to a variant allele frequency of 2%), the condition is defined as CHIP. Most people with CHIP have a mutation in an epigenetic regulator gene (DNMT3A, TET2, or ASXL1) and can remain stable for years.

Phase 3: MDS or CCUS. The clonal hematopoiesis expands further and becomes dominant in the bone marrow. This is often associated with additional somatic mutations—by the time clinical disease appears, the median number of mutations is 2 to 3 per patient. This phase meets the diagnostic criteria for either MDS or CCUS.

Phase 4: Secondary AML. The acquisition of more mutations leads to the selection of subclones of cells that cannot mature properly. When the proportion of these immature blast cells increases to 20% or more, the diagnosis changes to secondary acute myeloid leukemia (AML).

The paradox of MDS is that the founding mutation provides an advantage to the stem cells, allowing them to multiply, but a disadvantage to the more mature precursor cells, causing them to die prematurely and leading to low blood counts.

Key Mutation-Driver Genes in MDS

Research has identified several groups of genes that, when mutated, can drive the development of MDS. These genes are involved in critical cellular processes like RNA splicing, DNA methylation, histone modification, transcription regulation, DNA repair, cell signaling, and the cohesin complex.

Only six genes are mutated in at least 10% of MDS patients:

• SF3B1
• TET2
• SRSF2
• ASXL1
• DNMT3A
• RUNX1

Many other genes are mutated less frequently. Most of these mutations are a specific type (C-to-T transitions at CpG dinucleotides), suggesting they are simply related to the aging process. Mutations in spliceosome genes (like SF3B1, SRSF2, U2AF1) are usually early events that drive the clone to dominance. Mutations in DNA methylation and histone modification genes also drive clonal dominance, while other mutations contribute to the progression of the disease.

Pathophysiology of Specific MDS Subtypes

Different genetic mutations lead to different subtypes of MDS, each with its own characteristics and implications for patients.

MDS with Isolated del(5q)
This subtype is initiated by a deletion on the long arm of chromosome 5. This deletion leads to a situation called haploinsufficiency, where there is only one functional copy of several genes instead of two. This lack of genetic material explains the clonal expansion of cells, the macrocytic anemia (large red blood cells), and even why the drug lenalidomide is effective for these patients. Specifically, having only one copy of the CSNK1A1 gene makes the abnormal cells more sensitive to lenalidomide than healthy cells.

SF3B1-Mutated MDS
This subtype is characterized by the presence of ring sideroblasts in the bone marrow, ineffective red blood cell production, and macrocytic anemia. It generally has a relatively good prognosis, though many patients become dependent on blood transfusions. The SF3B1 mutation causes errors in RNA splicing, leading to the production of abnormal gene transcripts that are often degraded. This reduced production of normal proteins affects multiple genes, causing the disease's features.

MDS with SRSF2 or U2AF1 Mutations
MDS with mutations in the SRSF2 or U2AF1 genes are often associated with a poorer clinical outcome. These mutations cause different splicing errors than SF3B1, primarily leading to altered exon usage. They are almost always found in combination with other mutations. For example, the co-mutation SRSF2 (P95H) and IDH2 (R140Q) works together to drive cancer through coordinated alterations in both RNA splicing and epigenetic regulation.

Progression to Leukemia (Leukemic Transformation)

The evolution of MDS into acute myeloid leukemia (AML) is a process of clonal selection. Mutations that drive this transformation may already be present when MDS is first diagnosed but only expand later, typically under some kind of selection pressure, like from treatment.

The pattern of transformation can vary. For instance, MDS with an SF3B1 mutation often has a long, chronic phase, and only a minority of cases progress to AML, usually through acquiring additional mutations in genes like RUNX1 or EZH2. In contrast, MDS cases with combinations of mutations in SRSF2, U2AF1, RUNX1, STAG2, or IDH2 often start with a high number of blasts and gradually progress to AML, representing a clear continuum between the two diseases where the 20% blast threshold is the main distinguishing factor.

Inherited (Germline) Predisposition

While MDS are primarily sporadic diseases of older adults, there is growing evidence that a portion of patients have an inherited predisposition to developing myeloid cancers. This is more frequently, but not exclusively, observed in patients under the age of 50. This highlights the importance of family history and genetic counseling in certain cases.

What This Means for Patients: Clinical Implications

This detailed scientific understanding has direct and meaningful implications for patient care.

Precision Diagnosis: The modern WHO classification, which incorporates genetic testing, allows for a much more precise diagnosis than ever before. Knowing the specific genetic makeup of your MDS helps doctors accurately classify the disease and predict its likely behavior.

Prognostic Stratification: Tools like the IPSS-R scoring system, now enhanced by genetic information, help doctors estimate a patient's prognosis. This includes predicting the risk of the disease progressing to acute myeloid leukemia (AML) and overall survival. This information is crucial for making decisions about how aggressively to treat the disease.

Treatment Decisions: Genetics can directly guide therapy. The clearest example is for patients with MDS with isolated del(5q), who often respond exceptionally well to the drug lenalidomide. Understanding that other mutations (like those in TP53) are associated with poorer responses to treatment can help manage expectations and guide choices toward clinical trials or more aggressive therapies like stem cell transplantation.

Monitoring and Early Intervention: Understanding the stepwise progression from conditions like CHIP and CCUS to full-blown MDS opens the door for monitoring high-risk individuals and potentially intervening earlier to prevent progression.

Development of New Therapies: By identifying the specific genetic errors that cause MDS, researchers can develop targeted therapies designed to correct or counteract those specific errors, leading to more effective and less toxic treatments in the future.

Understanding the Limitations

While this review provides a comprehensive overview, it is important to understand its context. As a review article, it synthesizes existing knowledge but does not present new, original clinical trial data. The field of MDS genetics is rapidly evolving; new genes and interactions are still being discovered, and their full clinical significance is not yet always clear for every patient. Furthermore, the complexity of genetic interactions means that predicting the exact course of disease for an individual remains challenging. Finally, access to the advanced genetic testing described may be limited at some treatment centers.

Source Information

Original Article Title: Myelodysplastic Syndromes
Author: Mario Cazzola, M.D.
Publication: The New England Journal of Medicine (October 1, 2020;383:1358-74)
DOI: 10.1056/NEJMra1904794

This patient-friendly article is based on peer-reviewed research from a leading medical journal. It is intended for educational purposes to help patients understand their condition and should be discussed with a healthcare professional for personal medical advice.