Journal
LEUKEMIA
Volume 22, Issue 10, Pages 1828-1840Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2008.236
Keywords
JAK2 V617F; myeloproliferative neoplasms; Mpl (TpoR); EpoR; STAT signaling
Categories
Funding
- Fondation Salus Sanguinis
- Action de Recherche Concertee (ARC) MEXP31 of the Universite Catholique de Louvain
- Fondation contre le cancer
- Atlantic Philanthropies, New York
- de Duve Institute
- Fonds National de la Recherche Scientifique (FNRS), Belgium
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The BCR-ABL-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), entered the spotlight in 2005 when the unique somatic acquired JAK2 V617F mutation was described in >95% of PV and in 50% of ET and PMF patients. For the very rare PV patients who do not harbor the JAK2 V617F mutation, exon 12 JAK2 mutants were discovered also to result in activated forms of JAK2. A minority of ET and PMF patients harbor mutations that constitutively activate the thrombopoietin receptor (TpoR). In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2 V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L. The reasons for these differences are unknown. Exactly by which mechanism(s) one acquired somatic mutation, JAK2 V617F, can promote three different diseases remains a mystery, although gene dosage and host genetic variation might have important functions. We review the recent progress made in deciphering signaling anomalies in PV, ET and PMF, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.
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