Chronic Myeloproliferative Neoplasms

Chronic myeloproliferative neoplasms (MPNs; formerly chronic myeloproliferative disorders, CMPDs) are clonal diseases of hematopoietic tissue involving excess production of myeloid cells. This article focuses mainly on BCR::ABL1-negative MPNs: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).

Advances in molecular diagnosis have revealed important disease mechanisms. The somatic JAK2 V617F mutation was described in 2005. The c.1849G>T substitution in exon 14 replaces valine (Val, V) with phenylalanine (Phe, F) at protein position 617. Increased signaling activity promotes growth of the cellular clone.

JAK2 V617F is detected in most patients with PV and a substantial proportion with ET or PMF. Frequency depends on the disease and population studied; its absence does not exclude an MPN. When PV is suspected without V617F, other JAK2 variants, particularly exon 12, are investigated.

Other Molecular Markers

MPL encodes the thrombopoietin receptor. Its activating W515L and W515K variants replace tryptophan at position 515 with leucine and lysine, respectively. They can sustain pathological signaling and occur in some patients with ET and PMF. CALR mutations are also important. Absence of JAK2 cannot therefore be explained solely by MPL.

Some cases have no detected JAK2, CALR or MPL variant; other clonal markers and alternative causes of blood abnormalities are investigated when indicated. These tests do not replace a blood count, bone marrow morphology and other necessary investigations.

Interpreting JAK2 Results

• V617F is usually an acquired somatic change in a hematopoietic clone, rather than a variant inherited from parents. Other inherited predisposition factors may nevertheless exist.
• The mutant allele proportion in a sample can vary; it cannot be reduced to a heterozygous genotype of the whole person.
• A positive result supports a clonal process but does not independently determine the MPN type and may sometimes occur in clonal hematopoiesis without an established MPN.
• A negative result depends on assay coverage and sensitivity. Additional or repeat testing is ordered on clinical grounds, rather than automatically after a fixed interval.

Molecular markers form part of modern MPN diagnostic criteria but are assessed with clinical and morphological findings. Detecting JAK2 does not exclude a coexisting reactive cause of erythrocytosis, thrombocytosis or fibrosis. A hematologist makes the final assessment.