Abstract

Clonal hematopoiesis triggered by somatic mutations plays a central role in the pathogenesis of Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPNs). After the discovery of JAK2 and MPL mutations, continual technological advances have led to the identification of increasing numbers of genetic defects in MPN patients, most of them chromosomal aberrations such as deletions and acquired uniparental disomies. Although efforts to map the genetic lesions to single genes resulted in the discovery of defects in the TET2 and CBL genes, most of the target genes comprised in the chromosomal lesions still remain to be identified. In this review, the different genetic defects found in MPN and their relationships to each other and to disease pathogenesis are critically evaluated. At present, most of the evidence points to a random acquisition of phenotypic and non phenotypic mutations contributing to clonal heterogeneity in MPN. The origin of genetic instability in context of hereditary factors and the common JAK2 haplotype predisposing for the disease are discussed. Furthermore, we address how the choice of therapeutic approaches could be influenced by the genetic complexity.

Keywords: JAK2-V617F, oncogene, tumor suppressor, MPL, CBL, TET2, Pathogenesis, Chromosome, Neoplasms, Myeloproliferative neoplasms (MPN), clonal stem cell, hematopoietic system, production of blood cells, myeloid lineage, disease, thrombocythemia, primary myelofibrosis (PMF), fibrotic tissue, chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), phenotypes, morbidity, mortality, Bone marrow fibrosis, peripheral blood, hepatic failure, bleeding, portal hypertension, heart failure, Cytokine hypersensitivity, somatic mutations, exon, tyrosine kinases, receptor signaling, ligands, Transcription, growth, hyperphosphorylation, mitotic recombination, DNA, protein, polycythemia, Genetic factors, Oncogenic Mutations, autoregulatory properties, platelet, splenomegaly, splenic infarction, Tumor, amino acid, catalyze, Complex Regulator, Clonal, hypersensitivity, cascades, regulatory proteins, proto-oncogenes, neurofibromin, hydrolysis, guanosine triphosphate, heterozygous, cancer, Leukemia, thrombosis, death, clone, cytotoxic agents, single nucleotide polymorphism (SNP), genotyping, autosomal, density, microarrays