Académie royale de Médecine de Belgique


Vidéo et résumé Stefan N. Constantinescu

(Séance du 24 novembre 2012)


par St. CONTANTINESCU (UCL), invité.         

Chronic myeloid blood cancers are characterized by uncontrolled survival, proliferation and differentiation of progenitors that give rise to the mature red blood cells, platelets or white blood granulocytic cells. Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are initiated when a hematopoietic stem cell acquires mutations that frequently induce constitutive signaling via JAK2, STAT5 and STAT3 and that manifest phenotypically at the later committed progenitor levels. These diseases maintain a near-normal differentiation program, but the excessive cell numbers induce serious complications.  The vast majority of PV (98%), and 60% of the ET and PMF are associated with the unique acquired somatic JAK2 V617F mutation. 5-8% of ET and PMF are associated with activating mutations in the receptor for thrombopoietin (TpoR). The V617F mutation is localized in a special domain, caused pseudokinase, kinase-like, or kinase-light domain, which activates the adjacent tyrosine kinase domain, resulting in complexes between an activated JAK2 and cytokine receptors. The constitutive nature of signaling by JAK2 V617F and TpoR mutants leads to chromatin changes, which promote progression to leukemia. Progress in treatment with JAK2 inhibitors and perspectives of more specific approaches will be discussed.