Myeloproliferative Neoplasms

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Basics

Description

  • Myeloproliferative neoplasms (MPNs) are a group of clonal disorders that share a common cell of origin in the pluripotent hematopoietic stem cell.
  • MPNs are characterized by proliferation of cells of myeloid lineage—granulocytic, erythroid, megakaryocytic, or mast cell. They share common clinical features including risk of thrombosis, spleen and/or liver enlargement, and constitutional symptoms related to a hypermetabolic state.
  • The “classic” MPNs include chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). World Health Organization (WHO) MPN classification also includes chronic neutrophilic leukemia, chronic eosinophilic leukemia not otherwise specified (CEL-NOS), systemic mastocytosis, and MPN unclassifiable.
  • This topic focuses on the classic MPNs.
  • CML is characterized by the presence of Philadelphia chromosome (reciprocal translocation between chromosomes 9 and 22 resulting in a BCR-ABL fusion gene). This fusion gene mediates the uninhibited proliferation of myeloid precursor stem cells predominantly resulting in granulocytosis and excess granulocyte precursors.
  • The following three MPNs are characterized by varying degree of presence of JAK2 V617F mutation and are negative for BCR-ABL fusion gene:
    • PMF: JAK2 in about 50%; MPN characterized by marrow fibrosis, extramedullary hematopoiesis, and splenomegaly
    • ET: JAK2 in about 50%; MPN characterized by a clonal proliferation of megakaryocytes, leading to thrombocytosis
    • PV: JAK2 in 95%; MPN characterized by trilineage growth of hematopoietic stem cells with erythroid precursors predominating, leading to erythrocytosis

Epidemiology

Incidence
  • CML: 0.6 to 2.0/100,000/year; median age at diagnosis 66 years; male > female (1.6:1)
  • PMF: 0.2 to 0.5/100,000/year; median age at diagnosis 65 years; male = female
  • ET: 0.6 to 2.5/100,000/year; median age at diagnosis 60 years, second peak in younger patients at ~30 years; female > male (2:1)
  • PV: 1 to 2/100,000/year; male > female (1.3:1)

Etiology and Pathophysiology

  • CML: BCR-ABL1 gene leads to increased and unrestrained activity of the ABL tyrosine kinase resulting in an unchecked activation of downstream signaling pathways which have an antiapoptotic effect on the hematopoietic cells.
  • PMF: Progenitor hematopoietic stem cells undergo a clonal proliferation independent of growth factors likely due to activation of downstream intracellular pathways. The fibroblasts are nonclonal, and the increased fibrosis is driven by growth factors released by hematopoietic cells especially megakaryocytes.
  • ET: Thrombopoietin-induced megakaryocyte proliferation is uncontrolled due to a combination of increased sensitivity to thrombopoietin and decreased feedback regulation of the thrombopoietin levels by platelets allowing the platelet mass to expand.
  • PV: Gain-of-function mutation (JAK2) leads to increased erythrocyte production due to a downstream activation of proteins involved in cell proliferation and resistance to apoptosis. The JAK2 tyrosine kinase is downstream of the erythropoietin receptor and thus its constitutive activation makes the hematopoietic progenitor cell independent of erythropoietin.

Genetics
  • In >95% of MPNs, mutations driving the phenotype are on three genes: JAK2, calreticulin (CALR), and MPL; mutation occurring mutually exclusive manner
  • Philadelphia chromosome (BCR-ABL1 gene): translocation and fusion of the BCR gene on chromosome 22 and the ABL gene on chromosome 9; seen in all patients with CML
  • JAK2 mutations: gain-of-function point mutations in the tyrosine kinase domain of JAK2, causing a substitution of phenylalanine for valine at position 617 (JAK2 V617F), leading to unrestrained JAK2 activation with a deactivation of typical feedback mechanism. Seen in >95% of PV cases; 50% of ET and PMF cases
  • CALR frameshift mutation: CALR is an endoplasmic reticulum chaperone protein directing proper folding of proteins. This mutation may be seen in up to a third of patients of ET and PMF. These patients are seen to have a higher platelet count but lower risk of thrombosis.
  • Myeloproliferative leukemia virus (MPL) gene: gain-of-function point mutations found in 5–10% of patients with PMF and in 3–5% of those with ET. This encodes the thrombopoietin receptor MPL.

Risk Factors

  • Rare familial cases have been reported.
  • CML: exposure to ionizing radiation

Commonly Associated Conditions

  • Progression to acute myeloid leukemia; most common with CML
  • Thrombosis/hemorrhage

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