Myeloproliferative Neoplasms (MPNs) are chronic blood cancers originating in the bone marrow, the spongy tissue inside bones where blood cells are made. The acronym MPN stands for Myeloproliferative Neoplasm, describing the abnormal and uncontrolled growth of myeloid cells. These conditions are characterized by the overproduction of mature blood cells, including red blood cells, white blood cells, or platelets, which leads to various health complications. This overview provides an understanding of MPNs, from their biological origins to their diagnosis and management.
Defining Myeloproliferative Neoplasms
The biological process of MPNs begins with a somatic mutation in a hematopoietic stem cell within the bone marrow. These precursor cells are responsible for generating all mature blood cells. The term “myelo” refers to the bone marrow, and “proliferative” means to grow quickly, while “neoplasm” signifies an abnormal growth of cells. This genetic change provides the mutated stem cell with a selective growth advantage, leading to its clonal expansion.
The result is a hyperactive bone marrow that generates an excessive amount of one or more blood cell types. This overproduction can interfere with normal blood function. This abnormal cell growth is associated with mutations in one of three key genes: JAK2, CALR, or MPL. These genetic alterations activate signaling pathways, most notably the JAK-STAT pathway, which continuously signals the stem cells to proliferate.
Primary Subtypes of MPN
The classical MPNs are categorized into three distinct subtypes, based on the type of blood cell that is predominantly overproduced. These Philadelphia chromosome-negative MPNs—Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF)—have overlapping features but distinct clinical courses.
Polycythemia Vera (PV)
PV is the most common subtype, characterized by the overproduction of red blood cells. This causes the blood to thicken, slowing blood flow and elevating the risk of dangerous blood clots that can lead to stroke or heart attack. PV is nearly always associated with the JAK2 V617F mutation, found in over 95% of patients.
Essential Thrombocythemia (ET)
ET involves the excessive production of platelets, the cell fragments responsible for blood clotting. Despite the high platelet count, these platelets are often dysfunctional, leading to both clotting and bleeding issues. ET is considered the most indolent subtype and is associated with JAK2, CALR, or MPL mutations. The JAK2 mutation is present in about 50% to 70% of cases.
Primary Myelofibrosis (PMF)
PMF is considered the most aggressive subtype, characterized by the progressive build-up of scar tissue, or fibrosis, in the bone marrow. This scarring impairs the bone marrow’s ability to produce blood cells effectively, often leading to low blood counts (cytopenias), such as anemia. Atypical megakaryocytes proliferate abnormally, leading to the release of fibrotic growth factors. PMF frequently presents with JAK2, CALR, or MPL mutations, with JAK2 found in about 40% to 50% of patients.
Recognizing Common Indicators and Diagnosis
Many individuals with MPNs may not exhibit noticeable signs in the early stages, often first suspected after routine blood work. When symptoms appear, they are non-specific and can include profound fatigue, night sweats, unexplained weight loss, and generalized itching (pruritus). An enlarged spleen (splenomegaly) is also a common physical finding, as the spleen takes over some blood cell production when the bone marrow is compromised.
Diagnosis typically begins with a Complete Blood Count (CBC), which measures the levels of red blood cells, white blood cells, and platelets. A CBC showing persistently elevated levels of one or more cell lines is a strong indicator of an MPN. If initial blood tests are suggestive, specialized testing is performed to look for the characteristic genetic mutations.
Molecular testing focuses on the driver mutations, with the JAK2 V617F mutation being the most common target. Testing for CALR and MPL mutations is also routinely performed, especially if the JAK2 test is negative. A bone marrow aspiration and biopsy is often necessary to confirm the diagnosis, assess the cellularity of the marrow, and determine the degree of fibrosis. The biopsy allows a pathologist to examine the morphology of the blood-forming cells to definitively classify the MPN subtype.
Management and Therapeutic Approaches
The goal of MPN management is to control symptoms, reduce the risk of blood clots and bleeding, and slow disease progression, as a cure is not often possible with standard therapy. Treatment strategies are highly individualized and follow a risk stratification approach based on a patient’s age and history of blood clots.
Low-risk patients, particularly those with ET or PV, may be managed with a “watch-and-wait” approach, often supplemented with low-dose aspirin to reduce clotting risk. For PV, phlebotomy (the controlled removal of blood) is the standard treatment to keep the red blood cell count in a safe range.
For higher-risk patients or those with more advanced disease, cytoreductive therapy is used to lower the excessive blood cell counts. Hydroxyurea is a common oral medication that limits the bone marrow’s ability to produce blood cells and is used across all three MPN subtypes. Interferon-alpha is another medication that may be used to slow the production of blood cells, particularly in younger patients.
Targeted therapies, such as Janus kinase (JAK) inhibitors like ruxolitinib, are a significant advancement in treatment. These drugs work by blocking the overactive signaling pathway caused by the JAK2 mutation, helping to reduce spleen size and alleviate constitutional symptoms like fatigue and night sweats. The only potentially curative treatment for MPNs, particularly for high-risk PMF, is an allogeneic hematopoietic stem cell transplant, which replaces the diseased bone marrow with healthy donor cells.