Nadir Miyeloproliferatif Bozukluklar: Miyeloproliferatif Neoplazilerin Genetiği

Turkiye Klinikleri J Hematol-Special Topics 06/2013; 6(1):1-12.

ABSTRACT Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders originated from genetically transformed stem cells and characterized by myeloid hyperplasia and increased risk for leukemic
transformation. Since the discovery of JAK2-V617F mutation in 2005, our understanding on the molecular and genetic mechanisms underlying the initiation and prognosis of MPNs has been significantly improved. Unlike CML, for which diagnosis and treatment options almost completely rest upon the
BCR-ABL1 fusion gene, pathogenesis of BCR-ABL1-negative MPNs involves highly complex and interrelated processes. It has been shown that mutations in genes involved in cytokine receptor signaling including tyrosine kinases, in RNA splicing and epigenetic machinery as well as in those encoding crucial
transcription factors contribute to the MPN phenotype. Yet, there are many fundamental questions about
the pathogenesis of BCR-ABL1 negative MPNs waiting to be answered. Improvements in
genetic/genomic/epigenetic techniques and widespread use of them will provide an important opportunity in complete identification of somatic mutations, chromosomal rearrangements, and copy number alterations
associated with MPNs

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    ABSTRACT: The past 7 years have witnessed remarkable progress in our understanding of the genetics of BCR-ABL-negative myeloproliferative neoplasms (MPNs) and has revealed layers of unexpected complexity. Deregulation of JAK2 signaling has emerged as a central feature, but despite having biological activities that recapitulate the cardinal features MPNs in model systems, JAK2 mutations are often secondary events. Several other mutated genes have been identified with a common theme of involvement in the epigenetic control of gene expression. Remarkably, the somatic mutations identified to date do not seem to be acquired in any preferred order, and it is possible that the disease-initiating events remain to be identified. The finding of complex clonal hierarchies in many cases suggests genetic instability that, in principle, may be inherited or acquired. A common haplotype has been identified that is strongly associated with the acquisition of JAK2 mutations, but the cause of relatively high-penetrance familial predisposition to MPNs remains elusive. This review summarizes the established facts relating to the genetics of MPNs, but highlights recent findings and areas of controversy.
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