Histological and molecular classification of chronic myeloproliferative disorders in the age of JAK2: persistence of old questions despite new answers

Pathobiology. 2007;74(2):72-80. doi: 10.1159/000099120.

Abstract

The discovery of the Janus kinase 2 gain-of-function V617F mutation (JAK2(V617F)) provided a major breakthrough in the understanding of Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph(-) CMPD). Among haematologic neoplasm the mutation appears to be almost specific for Ph(-) CMPD but the different entities comprising polycythaemia vera (PV), essential thrombocythaemia and chronic idiopathic myelofibrosis (CIMF) are not discriminated by the mutation. It is unclear how the diversity with heterogeneous clinical and pathoanatomical presentations comes about. It has been suggested that differences in JAK2(V617F) gene dosage or different degrees to which the haematologic lineages are affected by the mutation could explain the heterogeneity of morphology and prognosis. Indeed the mutation mediates a PV-like phenotype but with regard to myelofibrosis JAK2(V617F) does not appear to be a causative factor. Megakaryocytes are homozygous in the majority of fibrotic CIMF and PV, whereas JAK2(V617F) heterozygosity is predominantly encountered in prefibrotic CIMF and essential thrombocythaemia but transition from hetero- to homozygosity with onset of fibrosis is rare. In conclusion, JAK2(V617F) provides a valuable adjunct to the diagnosis of Ph(-) CMPD, in particular with regard to discrimination from reactive proliferations, but the challenge of correct subtyping and hence prognostication persists for clinicians and bone marrow pathologists.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biopsy
  • Bone Marrow / pathology*
  • Chronic Disease
  • Diagnosis, Differential
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Genetic Markers
  • Humans
  • Janus Kinase 2 / genetics*
  • Molecular Diagnostic Techniques
  • Mutation*
  • Myeloproliferative Disorders / classification
  • Myeloproliferative Disorders / diagnosis*
  • Myeloproliferative Disorders / enzymology
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / pathology
  • Philadelphia Chromosome*
  • Polycythemia Vera / diagnosis
  • Polycythemia Vera / genetics
  • Predictive Value of Tests
  • Primary Myelofibrosis / diagnosis
  • Primary Myelofibrosis / genetics
  • Prognosis
  • Thrombocythemia, Essential / diagnosis
  • Thrombocythemia, Essential / genetics

Substances

  • Genetic Markers
  • JAK2 protein, human
  • Janus Kinase 2