Description

• Myeloproliferative neoplasms (MPNs) are a group of clonal disorders that all originate in the pluripotent hematopoietic stem cell. This topic focuses on chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).
  • The 2016 World Health Organization (WHO) MPN classification also includes chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia-not otherwise specified (CEL-NOS), and MPN-unclassifiable, all more rare.
  • CML is characterized by uninhibited proliferation of myeloid precursor cells.
  • PV is characterized by erythrocytosis.
  • ET is characterized by thrombocytosis.
  • PMF is characterized by bone marrow fibrosis and extramedullary hematopoiesis.
    • As MPNs share common origins, they often share common features, and they can transform into one another.
• The natural history can last decades, but each MPN carries the risk of complications.

Epidemiology

The median age of diagnosis is >60 years.

Incidence

• CML: 1.6/100,000/year
• PV: 0.8/100,000/year
• ET: 1.0/100,000/year
• PMF: 0.5/100,000/year

Etiology and Pathophysiology

Genetic mutations activating hematopoiesis result in proliferation of cells of myeloid, erythroid, and/or megakaryocyte lineages.

Genetics

• CML is characterized by a 9:22 translocation (the Philadelphia chromosome) resulting in the oncogenic BCR-ABL1 fusion gene producing the constitutively active tyrosine kinase leading to cell proliferation, particularly of granulocytes.
• PV, ET, and PMF share “driver” mutations, most often of JAK2, MPL, and CALR genes, that activate hematopoiesis. Mutation in one of these three genes is found in >90% of BCR-ABL negative MPNs.
  • Janus kinase 2 (JAK2) mutations: JAK2 specifically regulates hematopoiesis via erythropoietin (EPO), GM-CSF, thrombopoietin, growth hormone, leptin, and IL-3 and IL-5 signaling (1). Mutations constitutively activating the JAK2 protein lead to cell proliferation and prolonged survival.
    • JAK2 V617F mutations: 95% of PV, 55% of ET, and 65% of PMF cases (1)
    • JAK2 exon 12 mutations: 4% of PV cases (1)
  • Myeloproliferative leukemia protein (MPL) gene mutations: The MPL gene encodes the thrombopoietin receptor, which regulates hematopoietic stem cells, especially megakaryocytes; mutations can cause cell overproduction.
    • MPL mutations: 3% of ET, 5% of PMF (1)
  • Calreticulin (CALR) gene mutations: specific frameshift mutations of CALR, which encodes calreticulin protein, lead to activated hematopoiesis, particularly of the megakaryocyte lineage. The mechanism may be via constitutive activation of the thrombopoietin receptor (1).
    • CALR mutations: 25% of ET, PMF cases (1)

Risk Factors

• Any factor that increases risk of somatic mutations, such as ionizing radiation.
• Although a large majority of MPNs are due to somatic mutations, familial cases occur (1).
• PV, ET, and PMF can transform into one another.

Commonly Associated Conditions

• Thrombotic events (e.g., CVA, TIA, DVT, Portal Vein Thrombosis)
• Major and minor hemorrhagic events (e.g., acquired von Willebrand disease)
• Anemia
• Bone marrow fibrosis, osteosclerosis
• Extramedullary hematopoiesis
• Blast transformation into acute leukemia