Oncogenic mechanisms in myeloproliferative disorders

Abstract

Myeloproliferative disorders (MPDs) are clonal haematopoietic malignancies involving the abnormal proliferation of myeloid lineages. The World Health Organisation (WHO) classification of haematopoietic malignancies distinguishes MPDs from myelodysplastic/ myeloproliferative disorders and systemic mastocytosis. These malignancies frequently involve constitutive tyrosine kinase activity, resulting from either oncogenic fusion protein production or from point mutations. Chronic myelogenous leukaemia is the model used for studies of the consequences of such molecular defects. However, the heterogeneity of the clinical course of MPDs should be seen in a more rationale conceptual framework, including the many molecular events associated with these diseases. This review focuses on the various tyrosine kinase-related molecular mechanisms underlying both MPDs and rare diseases with myeloproliferative features. We pay particular attention to the newly identified JAK2 V617F mutation in polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional molecular mechanisms.

Pathogenetic insight and prognostic information from standard and molecular cytogenetic studies in the BCR-ABL-negative myeloproliferative neoplasms (MPNs)

“…These results imply a role for cooperating mutations in the pathogenesis of JAK2 V617F-positive MPNs and support the hypothesis that dosage of JAK2 contributes to the disease phenotype in which an increased constitutive activation of JAK2 provides a proliferative advantage. 138 Cytogenetics, when combined with JAK2 mutational screening, has also provided evidence of a common clonal origin for at least some cases of MPNs and AML and for the fact that JAK2 mutations may not be the initiating event. Theocharides et al, 139 for example, reported a single case with JAK2-V617F-positive PMF in which JAK2-V617F was absent from the blasts at the time of transformation.…”

Centrosomal targeting of tyrosine kinase activity does not enhance oncogenicity in chronic myeloproliferative disorders

“…1 Typically, disease progression in CMD is reflected by an increase of immature cells and growing chromosomal instability. Constitutive activation of tyrosine kinases ABL, FGFR1, JAK2, PDGFRa or PDGFRb has been identified as a common underlying pathomechanism in CMD.…”

“…Constitutive activation of tyrosine kinases ABL, FGFR1, JAK2, PDGFRa or PDGFRb has been identified as a common underlying pathomechanism in CMD. [1][2][3][4][5] Structurally, with the exception of ABL these tyrosine kinases belong to the receptor tyrosine kinase family and consist of an extracellular ligand binding domain, a transmembrane domain, an often autoinhibitory cytoplasmic juxtamembranous domain and a catalytically active C-terminal domain.…”

The 2006 → 2008 European Clinical, Molecular and Patholobiogical (2008 ECMP) Classification and the 2007 WHO Revised Criteria for Myeloproliferative Neoplasms

“…The 2008 ECMP classification separated the JAK2 wild type MPN into MPL mutated ET/MF as the second and JAK2 wild type hypercellular ET associated with primary granulocytic megakaryocytic myeloproliferation (PMGM) as the third distinct MPN disease. [16,48,49]. [22][23][24][25][26][27][28][29][30] and the 2008 ECMP classification respectively are based on three specific bone marrow histology criteria: 1) the presence of large dysmorphic megakaryocytes with immature cytoplasm and immature cloud-like nuclei not seen in ET and PV, 2) increased granulopoiesis but never disturbed in maturation and 3) no features of PV with relatively decreased erythropoiesis.…”