Myeloproliferative Neoplasms — Polycythaemia Vera, ET, Myelofibrosis and the JAK2 Story

Myeloproliferative neoplasms (MPNs) arise from a mutated haematopoietic stem cell that keeps producing mature, functioning cells of one or more myeloid lines. This is the difference from acute leukaemia (blasts) and from myelodysplasia (ineffective, dysplastic production). The four classic MPNs are chronic myeloid leukaemia (CML), polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF).

The key split is genetic: CML is BCR-ABL1 positive (Philadelphia chromosome), whereas PV, ET and PMF are BCR-ABL1 negative and driven by mutations in JAK2, CALR or MPL — all of which switch on the same JAK-STAT signalling pathway. CML is covered with the other leukaemias in leukaemias classification.

• JAK2 V617F — a gain-of-function mutation of a cytoplasmic tyrosine kinase. It is found in about 70% of all MPNs: over 90% of PV, roughly 50–60% of PMF and about 50% of ET. It is not specific to PV — it is common to all three BCR-ABL1-negative MPNs.
• JAK2 exon 12 — found in about 5% of PV patients who are JAK2 V617F negative; not seen in ET or PMF.
• CALR (calreticulin) exon 9 — the gene sits on chromosome 19; calreticulin is a calcium-binding endoplasmic-reticulum chaperone. Mutations occur in ET and PMF but not PV.
• MPL (W515L/K) — the thrombopoietin receptor gene; seen in ET and PMF, with a higher frequency in PMF than in ET. MPL mutation carries a greater thrombotic risk than JAK2 V617F.
• Triple-negative — about 10–15% of ET and PMF lack all three driver mutations; triple-negative PMF has a worse prognosis, while CALR exon 9 mutation is associated with better survival in PMF.

PV is a clonal erythrocytosis with suppressed erythropoietin. The current diagnostic framework (WHO 5th edition and the International Consensus Classification) rests on three major criteria and one minor criterion:

• Erythropoietin is low in PV but normal or high in secondary polycythaemia (hypoxia, tumours, EPO-secreting lesions) — the quickest discriminator.
• Marrow morphology became a major criterion in the 2016 revision so that early PV is not missed; thresholds were also lowered and made gender specific.
• Always exclude secondary causes first: chronic hypoxia and EPO-secreting tumours raise erythropoietin, unlike PV.

Treatment aims at preventing thrombosis. Patients are risk-stratified: low risk = age 60 or below and no previous thrombosis; high risk = age above 60 or any previous thrombotic event.

ET is an MPN dominated by megakaryocytes and platelets. The WHO diagnostic platelet threshold was lowered from 600 to 450 × 10⁹/L in the 2016 revision. The marrow shows proliferation mainly of the megakaryocytic line, with enlarged, mature megakaryocytes with hyperlobulated nuclei and no significant increase or left shift of granulopoiesis or erythropoiesis.

• Mutations: JAK2 V617F in about 50–70%, CALR in 20–25%, MPL in 3–8%, triple-negative in 10–25%.
• Complications: arterial and venous thrombosis and bleeding (acquired von Willebrand disease at very high platelet counts); vasomotor symptoms such as headache and erythromelalgia.
• Pitfall: 'false' ET is often pre-fibrotic myelofibrosis — the reason marrow morphology matters.
• Treatment by risk: very low/low risk (age ≤ 60, no thrombosis) → low-dose aspirin or observation; high risk (age > 60 or thrombosis) → hydroxyurea plus low-dose aspirin. Prognosis is generally good, with near-normal life expectancy.

Primary myelofibrosis (PMF) is characterised by extramedullary haematopoiesis and bone marrow fibrosis. Fibrosis replaces haematopoietic marrow and blood formation shifts to the spleen and liver, producing marked splenomegaly. The peripheral blood shows leukoerythroblastosis (immature white and nucleated red cells) with teardrop-shaped red cells (dacrocytes) and poikilocytosis. The classic exam clue is a dry tap — the marrow aspirate yields little or no material, and the trephine biopsy shows fibrosis with atypical megakaryocytes.

• Mutations: JAK2 V617F ~50–60%, CALR and MPL in many of the rest; ~10–15% are triple-negative.
• Stages: an early pre-fibrotic phase (marrow shows megakaryocyte atypia without much fibrosis) precedes overt fibrotic disease; PV and ET can also progress to post-PV / post-ET myelofibrosis, with the same blood picture.
• Treatment: asymptomatic low-risk patients — observation; intermediate/high-risk disease — ruxolitinib (COMFORT trials: smaller spleen, fewer symptoms); allogeneic haematopoietic cell transplantation is the only potentially curative option for high-risk disease.

CML is the odd one out: BCR-ABL1 fusion from the reciprocal translocation between the long arms of chromosomes 9 and 22 (shortened chromosome 22 = the Philadelphia chromosome) makes a constitutively active tyrosine kinase. It is managed with tyrosine-kinase inhibitors: imatinib first-generation; nilotinib and dasatinib second-generation (both superior to imatinib in achieving cytogenetic and molecular remission in the ENESTnd and DASISION trials). The three BCR-ABL1-negative MPNs are therefore sometimes called the Philadelphia-negative MPNs.