Molecular and genetic bases of myeloproliferative disorders: questions and perspectives.
The discovery of the JAK2V617F mutation followed by the discovery of JAK2 exon 12 and MPLW515 mutations has completely modified the understanding, diagnosis, and management of the classic myeloproliferative disorders (MPDs), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Nonetheless, genetic defects have not yet been identified in about 40% of ET and PMF. There is now strong evidence that these mutations are the oncogenic events that drive these disorders and are responsible for most biologic and clinical abnormalities. In addition, there are convincing data indicating that the number of JAK2V617F copies (homozygosity vs. heterozygosity) is important in explaining how a single mutation can be associated with several disorders. However, it is still uncertain whether these mutations are sufficient to explain the full development, heterogeneity, and progression of MPD, or if other genetic or epigenetic events are also necessary. In this review, we discuss different hypothetical models of MPD pathogenesis supported by recent findings. Further characterization of the molecular events operating in these disorders will be essential in fully understanding their pathogenesis and in developing new therapeutic approaches.
Plo
Isabelle
I
INSERM U790, Villejuif, France Institut Gustave Roussy, 94805 Villejuif, France.
Vainchenker
William
W
D000818:Animals; D018450:Disease Progression; D005091:Exons; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis* / Q000235:genetics*; D011087:Polycythemia Vera / Q000175:diagnosis / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000235:genetics*; D013920:Thrombocythemia, Essential / Q000175:diagnosis / Q000235:genetics*
C507924:JAK2 protein, human; D053614:Janus Kinase 2