Hemopoiesis in Ph-negative chronic myeloproliferative disorders

Chronic myeloproliferative disorders (cMPDs) are clonal hemopoietic malignancies arising at the multipotent stem cell level. These conditions are characterized by increased blood count, marrow hyperplasia and extramedulary hemopoiesis. Vascular events might complicate their course, and transformation to either acute leukemia or myelofibrosis can finally occur. Among cMPDs, Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) belong to the group of Ph-negative cMPDs. Although they share common pathogenetic features, these entities have a quite different prognosis. The common pathogenetic basis of Ph-negative cMPDs was recognized long ago, and it was suggested that a stimulating factor might enhance bone marrow hemopoietic activity. Hemopoietic progenitors from cMPDs show hypersensitivity to low levels of a variety of hemopoietic cytokines. The independency of erythroid precursors from erythropoietin became the first surrogate marker of an abnormal hemopoietic clone. This clone is characterized by increased proliferation and survival, as well as by decreased apoptosis, leading to the accumulation of mature blood cells that additionally show a phenotype of activated cells. Recently four independent groups have described an activating point mutation in the JAK2 kinase as a key pathogenetic event in Ph-negative cMPDs. JAK2 is a tyrosine kinase that acts as a second intracellular messenger for many hemopoietic cytokine receptors. It is now believed that jacking up hemopoiesis can explain many features of myeloproliferation. Interestingly, some features are associated with intracellular levels of mutated JAK2 (the "dosage hypothesis"). The mutation in JAK2 kinase is not an example of a genetic defect leading to a single disease, since it occurs in many other myeloid disorders, and probably represents a secondary hit in a multistep ongogenetic process. Nevertheless, it has changed the way we approach cMPD patients and has clarified many aspects of their biology.