The classification of blood cancers can be complex, particularly those originating in the bone marrow, which are broadly known as myeloid disorders. These conditions arise from an acquired change in hematopoietic stem cells, which produce all mature blood components. Myelofibrosis (MF) and Myelodysplastic Syndromes (MDS) are often confused because both affect the bone marrow’s ability to produce healthy blood cells. However, their underlying biological mechanisms and official classifications are fundamentally different. Understanding the core pathology of each condition clarifies why Myelofibrosis is not considered a Myelodysplastic Syndrome.
Defining Myelodysplastic Syndromes
Myelodysplastic Syndromes (MDS) are clonal disorders characterized by ineffective hematopoiesis—the bone marrow’s failure to produce effective blood cells. The defining feature of MDS is dysplasia, meaning developing blood cells have an abnormal appearance, structure, and maturation. This abnormality can affect one, two, or all three major blood cell lines: red cells, white cells, and platelets. The presence of these morphologically abnormal cells signals a defect in the stem cell’s ability to mature correctly.
Ineffective production results in cytopenia, or low counts of mature blood cells in the peripheral blood. Patients often experience anemia, frequent infections, or easy bruising due to low counts of red cells, white cells, and platelets, respectively. MDS is a disease of quality over quantity; the bone marrow is often cellular, but the cells produced are defective and die prematurely. MDS also carries a variable risk of progression to Acute Myeloid Leukemia (AML).
Molecularly, MDS is frequently associated with mutations in genes that regulate RNA splicing, such as SF3B1 or SRSF2. These genetic changes disrupt the normal maturation pathway, leading to abnormal development and ineffective cell production. The primary pathology is the abnormal shape and function of the precursor cells, which ultimately leads to bone marrow failure.
Myelofibrosis: A Myeloproliferative Neoplasm
Myelofibrosis (MF) is classified as a Myeloproliferative Neoplasm (MPN), meaning a bone marrow cancer characterized by proliferation or overgrowth. Unlike the failure of cell quality seen in MDS, MF is initially defined by the excess production of abnormal cells. This involves the uncontrolled expansion of an abnormal clone of hematopoietic stem cells, leading to the overproduction of specific cell types, particularly megakaryocytes.
These abnormal megakaryocytes release excessive growth factors, such as Transforming Growth Factor-beta (TGF-\(\beta\)), into the bone marrow microenvironment. These signaling molecules stimulate non-cancerous fibroblasts to lay down scar tissue, a process called bone marrow fibrosis. The resulting dense scarring progressively replaces normal blood-forming tissue, physically impeding healthy hematopoiesis.
Scarring causes the bone marrow to fail, forcing the body to attempt blood production elsewhere, a phenomenon called extramedullary hematopoiesis. This often occurs in the spleen and liver, commonly resulting in an enlarged spleen (splenomegaly), a hallmark of MF. The disease is strongly linked to mutations in cell signaling genes, including JAK2, CALR, or MPL, found in the majority of patients.
Why They Are Grouped as Myeloid Neoplasms
Despite the distinct pathologies of dysplasia (MDS) versus proliferation (MF), both conditions are categorized as Myeloid Neoplasms. This grouping is based on their shared site of origin and cell lineage. Both diseases begin with an acquired mutation in the myeloid stem cell, located within the bone marrow.
The myeloid stem cell is the progenitor for red blood cells, platelets, and most types of white blood cells. A cancerous change in this foundational cell means the resulting disease is defined as a myeloid malignancy, regardless of whether it causes ineffective cell production or overproduction and scarring. International diagnostic guidelines, such as the WHO Classification system, recognize this shared ancestry and cellular compartment origin.
Key Distinctions in Disease Progression and Pathology
The fundamental difference between MDS and MF lies in the dominant pathological process. MDS is characterized by dysfunctional cell development, creating poor-quality, misshapen cells that cause peripheral cytopenias from the outset.
In contrast, MF is initially characterized by an overgrowth of abnormal cells that trigger a scarring reaction (fibrosis). This proliferation and subsequent fibrosis mechanically displace normal blood production. The genetic drivers reinforce this distinction: MF is associated with JAK2/CALR/MPL mutations that promote cell growth, while MDS involves splicing factors like SF3B1 that disrupt cell maturation.
Clinically, these underlying mechanisms lead to different presentations. MF is frequently accompanied by a significantly enlarged spleen (splenomegaly) due to extramedullary hematopoiesis, which is rare in early MDS. Although both conditions can progress to bone marrow failure and Acute Myeloid Leukemia, their initial trajectories—chronic ineffective production versus chronic overproduction and scarring—remain distinct biological processes.