Myeloproliferative neoplasms

The myeloproliferative neoplasms (MPN) are a group of clonal haematological diseases, whose characteristic feature is proliferation of one or more of the myeloid lineages (Fig 1). The four disorders that are most commonly included under MPN are listed in Table 1. Evidence is emerging that shows MPN is the result of various acquired mutations, which permanently activate genes (often coding for tyrosine kinases) that regulate cell proliferation. These mutations are better defined for some conditions than others. The more commonly encountered MPN and their associated lesions are shown in Table 1.

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Fig 1.

Haematopoiesis and the lineages that are predominantly affected in MPN. Myeloid haematopoiesis derives from pluripotent myeloid stem cells in the marrow, which give rise to the erythroid, megakaryocyte (platelet), granulocyte (neutrophil, eosinophil and basophil) and monocyte lineages. The point in this hierarchy at which MPN-associated mutations occur could partially determine which cells are predominantly over-produced, giving rise to the different clinical phenotypes of the MPN. BFU = burst-forming unit; CFU = colony-forming unit; E = erythroid; Meg = megakaryocytic; GM = granulocyte-monocyte; G = granulocytic; M = monocytic; Eo = eosinophilic; Ba = basophilic.

Of these, chronic myeloid leukaemia (CML) is the best understood at a molecular level. The translocation known as Philadelphia chromosome t(9;22) results in the ABL gene from chromosome 9 being transferred to chromosome 22. The product of this translocation (BCR-ABL) is an oncoprotein that has increased tyrosine kinase activity, which results in deregulated proliferation of leukaemic myeloid cells. Targeted treatment (with tyrosine kinase inhibitors such as imatinib) blocks BCR-ABL and produces very durable remissions (now of more than 10 years) in the majority of patients with CML — a huge improvement in outcome for this condition.

The MPN most commonly seen by non-haematologists — essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF) — are those associated with the Janus-associated kinase 2 (JAK2) V617F mutation. JAK2 is a signalling protein whose normal role is to activate cell proliferation following the binding of erythropoietin to its receptor (Fig 2). The activating V617F mutation leads to a constant ‘on switch’ that drives proliferation of myeloid precursors. How a single mutation results in three clinical phenotypes (and how some patients have the disease without the mutation) is likely to depend on the roles of other, some as-yet-unidentified, mutations and is currently under investigation.¹

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Fig 2.

Regulation of haematopoiesis by the erythropoietin (EPO) and thrombopoietin (TPO) receptors (EPO-R and TPO-R). The erythrocyte and platelet growth factors erythropoietin and thrombopoietin stimulate cell growth by binding cell surface receptors on haematopoietic progenitor cells. Receptor ligation leads to phosphorylation of the JAK2 tyrosine kinase and recruitment and activation of STATs. Activated, dimerised STATs pass into the nucleus, where they regulate the expression of genes that are required for cell-cycle activation and cell proliferation. Mutations in the JAK2 gene that result in constitutive activity are associated with PV, ET and PMF. Mutations in the MPL gene, coding for the TPO-R, are found in ET. CML = chronic myeloid leukaemia; EPO = erythropoietin; ET = essential thrombocythaemia; JAK2 = Janus-associated kinase 2; MPL = myeloproliferative leukemia; P = phosphorous; PMF = primary myelofibrosis; PV = polycythaemia vera; STAT = signal transducers and activators of transcription; TPO = thrombopoietin.

Polycythaemia vera

Polycythaemia refers simply to a raised haematocrit (HCT). It is important to note that the diagnosis is based on the haematocrit and not the haemoglobin concentration. In PV, the cause of the raised HCT is a primary marrow disorder resulting in red cell overproduction.

Polycythemia might also be secondary or apparent. In secondary polycythemia, excess red blood cells are produced in response to an increase in erythropoietin concentrations in the blood. In turn, an increase in erythropoietin can be seen in patients with chronic hypoxia (from congenital cyanotic heart disease or severe pulmonary disease) or, occasionally, because of excess erythropoietin production resulting from a tumour, most commonly renal cell cancer.

In apparent or relative polycythemia the red cell mass is normal but the plasma volume is reduced from causes such as diuretic use, obesity, smoking or alcohol excess (Table 2).

These alternative causes of polycythemia are not discussed further here. Distinguishing between PV and the other possible causes of a raised haematocrit is important because the outcome in PV is improved by treatment that reduces the haematocrit, whereas there is little evidence for venesection in secondary polycythaemia. As almost 100% of patients with PV are positive for a JAK2 mutation, diagnosis has become much simpler in recent years.

The incidence of PV is 0.7–2.6 per 100,000 per year, with a slight male predominance (M:F, 1.2:1) and a median age of 55–60 years.

Essential thrombocythaemia

Essential thrombocythaemia is a disorder of the megakaryocyte lineage. Given the prevalence of reactive thrombocytosis, diagnosis is often difficult. In the absence of the JAK2 V617F or other clonal mutation, it is essentially one of exclusion.

To meet the World Health Organisation (WHO) 2008 guidelines for diagnosis,² the patient must meet all four of the following criteria:

1. sustained (during the time of investigation) platelet count ≥450 × 10⁹/l

2. bone marrow biopsy showing proliferation of megakaryocytes with increased numbers of enlarged mature megakaryocytes

3. failure to meet the WHO criteria for other myeloproliferative neoplasms

4. carry either the JAK2 V617F mutation (present in about 50% of cases) or another clonal marker, or have no evidence of reactive thrombocytosis (see Table 2).

Incidence is estimated at 0.6–2.5 per 100,000 per year. There is no sex predominance and the majority of cases present in patients aged 50–70 years.

Primary myelofibrosis

In PMF, as in ET, the clonally proliferating cells are mostly abnormal megakaryocytes. The release of cytokine derived from the clone causes reactive deposition of fibrous connective tissue, leading to the characteristic features of the disease. Replacement of the normal bone marrow space with fibrous tissue prevents normal haematopoiesis and leads to anaemia and, eventually, pancytopenia (although peripheral blood counts, especially platelet counts, can be high early in the disease). Abnormal, ineffective extramedullary haematopoiesis is probably a partial attempt to correct for the loss of marrow function and often leads to massive splenomegaly. Systemic features, secondary to cytokine release, are common and include fevers, weight loss, anorexia and sweats. The replacement of the marrow by fibrosis results in the displacement of immature cell forms, such as nucleated red cells and myelocytes, into the peripheral blood (a leucoerythroblastic picture). The passage of normal erythrocytes through the narrowed fibrotic marrow spaces distorts them, generating the classic ‘tear-drop’-shaped red cells.

Incidence is equal in both sexes at 0.5–1.5 per 100,000 per year and the most common age of onset is 50–60 years. In addition to the primary disease, myelofibrosis can also occur secondary to ET or PV. Myelofibrosis can also be a feature of other malignancies, such as Hodgkin lymphoma, when there is marrow involvement.

Summary

The myeloproliferative neoplasms that are associated with the JAK2 mutation are a heterogeneous group of disorders. The additional mutations that result in the clinical phenotype are still the subject of research. As more than one mutation is involved, and as JAK2 has a necessary physiological role (unlike BCR-ABL), the development of targeted therapy remains a challenge. Although new drugs are being developed, treatment at present is predominantly with agents that have been in use for many years. An understanding of the need to control the thrombotic risk has, however, led to improved survival rates such that ET and PV can be seen as chronic diseases.