Myeloproliferative neoplasms

Abstract

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.

Keywords: JAK2; myelofibrosis; myeloproliferative; polycythaemia; thrombocytosis.

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.

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.