Pathogenetic and clinical impact of JAK2 mutations in chronic myeloproliferative diseases

Abstract

Myeloproliferative diseases (MPD) are characterized by the clonal expansion of mature myeloid cells. A reciprocal translocation between chromosome 9 and 22 is responsible for chronic myeloid leukaemia but not for the so-called Philadelphia Chromosome/BCR-ABL-negative MPDs. With the detection of mutations in the gene of the Janus kinase 2 (JAK2) in 2005, a specific genetic aberration was also found in BCR-ABL-negative MPD samples. These mutations lead to a constitutive activation of JAK2, which results in unlimited growth of haematopoietic precursor cells. Nowadays it is known that these mutations can be found at different frequencies in primary myelofibrosis, polycythemia vera and essential thrombocythemia. The precise role of the JAK2 mutations, however, in the pathogenesis of these diseases is not fully understood and some theories will be discussed. For the treatment of BCR-ABL-negative MPDs the inhibition of the hyperactive JAK2 seems to be promising. Several phase I and II studies investigating the effect of JAK-inhibitors are currently ongoing. In some preliminary data it has been shown that they effectivly reduce spleen size, leucocyte count and lead to a gain of body weight and a relief of constitutional symptoms. However, these results are preliminary, patient numbers are small, many data on other myelofibrosis-associated parameters are not evaluated yet and most of the patients in these clinical trials suffered from myelofibrosis. Although these preliminary data are promising, the effect in PV and ET as well as the long-term effect of these novel kinase inhibitors has to be reevaluated in the future.