What is a myeloproliferative neoplasm (MPN)?

What is a Myeloproliferative Neoplasm (MPN)?

Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders characterized by excessive production of one or more mature myeloid cell lineages in the bone marrow and blood. 1

Core Disease Characteristics

MPNs arise from acquired genetic driver mutations that cause constitutive activation of myeloid cytokine receptor signaling pathways, particularly the JAK-STAT pathway. 2, 3 These disorders result in:

• Uncontrolled proliferation of red blood cells, white blood cells, or platelets 4
• Chronic inflammation with elevated inflammatory signaling throughout the disease course 4, 5
• Increased thrombotic risk due to excessive cell production and abnormal signaling 4
• Risk of leukemic transformation and progression to acute myeloid leukemia 1

Classification of MPNs

The World Health Organization recognizes four main categories: 6

1. Chronic Myeloid Leukemia (CML)

• Strongly associated with the BCR::ABL1 gene translocation 4, 2

2. Classical Philadelphia-Negative MPNs

• Polycythemia Vera (PV): Characterized by increased red blood cell mass; hemoglobin >18.5 g/dL in men or >16.5 g/dL in women 1
• Essential Thrombocythemia (ET): Characterized by elevated platelet counts 1
• Primary Myelofibrosis (PMF): Characterized by bone marrow fibrosis and extramedullary hematopoiesis 1

These three disorders are typically accompanied by mutations in JAK2 (V617F or exon 12), MPL, or CALR genes. 1, 4 More than 90% of PV patients have JAK2 mutations, while approximately 60% of ET and PMF patients carry these mutations. 1

3. Non-Classical Philadelphia-Negative MPNs

• Chronic Neutrophilic Leukemia (CNL): Involves CSF3R gene mutations 4, 6
• Chronic Eosinophilic Leukemia: Rare eosinophil-predominant disorder 6

4. MPN, Unclassifiable (MPN-U)

• Cases not fulfilling diagnostic criteria for other specific entities 6
• Includes early-phase MPNs, advanced fibrotic cases, and disorders obscured by inflammatory or neoplastic conditions 6

Molecular Pathogenesis

The unifying molecular mechanism involves chronic activation of STAT transcription factors, particularly STAT5B, leading to sustained myelopoiesis. 2 Key genetic alterations include:

• Driver mutations: JAK2 V617F, JAK2 exon 12, MPL, CALR, CSF3R 3
• Cooperating mutations: Frequently detected in genes involved in epigenetic methylation, mRNA splicing, transcription regulation, and signal transduction 3
• Germline predisposition factors: Influence disease initiation and progression 3

Clinical Implications

MPNs occupy a spectrum between chronic inflammatory disease and cancer. 5 They share characteristics with both:

• Cancer features: Clonal proliferation, risk of leukemic transformation 1, 6
• Inflammatory disease features: Chronic inflammation, symptom burden (pruritus, night sweats, fatigue), dependency on immune system dysregulation 5

The primary treatment goals are to induce remission, improve quality of life and survival, and reduce complications including thrombosis, vascular events, and leukemic transformation. 4

Common Pitfalls

• Do not confuse PV with secondary polycythemia: PV requires JAK2 mutation or other molecular markers plus bone marrow findings; secondary polycythemia has elevated erythropoietin levels 1, 7
• Recognize that inflammatory markers (NLR, PLR, SII) are significantly elevated in PV compared to secondary causes, which can aid in diagnosis when molecular testing is unavailable 7
• Understand that MPN behavior aligns more with chronic inflammatory disease than typical malignancy, requiring long-term management strategies similar to autoimmune conditions 5