Description

• Myeloproliferative neoplasms (MPNs) are a group of clonal disorders that share a common cell of origin 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 significantly more rare (1); mastocytosis reclassified out of MPN (1)
• CML is characterized by uninhibited proliferation of myeloid precursor cells.
• PV is characterized by erythrocytosis, ET is characterized by thrombocytosis, and PMF is characterized by bone marrow fibrosis and extramedullary hematopoiesis.
• The natural history can last decades, but each MPN carries the risk of complications, such as thrombotic events, as well as transformation into acute leukemia or bone marrow fibrosis.

Epidemiology

Increasing age. MPNs median age of diagnosis is >60 years.

Incidence

• CML: 1.6/100,000/year
• PV: 0.84/100,000/year
• ET: 1.03/100,000/year
• PMF: 0.47/100,000/year

Etiology and Pathophysiology

MPNs result from genetic mutations activating hematopoiesis, resulting 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. The BCR-ABL1 fusion protein is a 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, IL-3 and IL-5 signaling. JAK2 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
  • JAK2 exon 12 mutations: 4% of PV cases
• Myeloproliferative leukemia protein (MPL) gene mutations: The MPL gene encodes the thrombopoietin receptor, which regulates hematopoietic stem cells, especially megakaryocytes; thrombopoietin receptor mutations can cause cell overproduction.
  • MPL mutations: 3% of ET and 5% of PMF cases
• Calreticulin (CALR) gene mutations: specific frameshift mutations in the CALR gene, which encodes calreticulin protein, lead to activated hematopoiesis, particularly of the megakaryocyte lineage. The mechanism may be via constitutive activation of the thrombopoietin receptor; this is an active area of research.
  • CALR mutations: 25% of ET and PMF cases
• As more driver mutations have been identified, they have been classified into mutations that appear “restricted,” in that they only result in MPNs, and mutations that are “unrestricted,” in that they can also be implicated in other myeloid neoplasms. JAK2, MPL, and CALR are considered “restricted” mutations.

Risk Factors

• Any factor that increases risk of somatic mutations, such as ionizing radiation
• The large majority of MPNs are due to somatic mutations, familial cases have been described.
• PV, ET, and PMF share mutations and can transform into one another.

Commonly Associated Conditions

• Thrombotic events (CVA, DVT, etc.)
• Major and minor hemorrhagic events (acquired von Willebrand disease)
• Anemia, bone marrow fibrosis, osteosclerosis
• Blast transformation into acute leukemia
• Extramedullary hematopoiesis