Molecular Genetics of Myeloproliferative Disorders

Abstract

The myeloproliferative neoplasms (MPNs) are a group of clonal stem cell disorders characterised by increased proliferation of one or more cell lines. The 2008 World Health Organization classification of the four major MPNs includes chronic myeloid leukaemia, polycythaemia vera, primary myelofibrosis and essential thrombocythemia. In recent years, the research and utilisation of molecular markers have been paving the way for a better understanding of the MPNs for pathophysiology, classification, prognosis and treatment. With the introduction of the BCR/ABL fusion 1 gene and the JAK 2 mutation involving the tyrosine kinase pathways, it is now used in evaluating patients for diagnosis, prognosis and enhancing current practices. More and more molecular markers (MPL, TET2, LNK, CBL, IDH1 and IDH2) are being identified with the hope of having a better understanding for clinical assessment and management of these neoplasms. The importance for patient care is about understanding the role of these molecular mutations in the MPNs and what the future is for prognosis and treatment of patients diagnosed with these disorders. Key Concepts: The myeloproliferative neoplasms are clonal stem cell disorders due to unregulated cell production. The MPNs have increased tyrosine kinase involvement with an increase of cell proliferation and a loss of apoptosis. The BCR/ABL fusion gene1 plays a critical role in the pathogenesis of chronic myeloid leukaemia. The BCR/ABL fusion gene is the reciprocal translocation between the chromosomes 9 and 22. The MPNs that do not present with the BCR/ABL mutation are referred to the BCR/ABL negative neoplasms. Tyrosine kinase activation involves signal transduction in the proliferative pathways. JAK kinase is involved in myeloid cell proliferation and differentiation. JaK2 mutation results in a ‘gain of function’ for the signalling molecule of the tyrosine kinase pathway. Jak2 is present in most patients with PV, ET and PMF. MPL, LNK, TET2, CBL, ASX‐L1,IDH1/IDH2, EZH2, DNMT3 and IKZF1 are currently known mutations in BCR/ABL negative MPNs.