Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: possible relationship with FKBP51 overexpression.
Komura E., Chagraoui H., Mansat de Mas V., Blanchet B., de Sepulveda P., Larbret F., Larghero J., Tulliez M., Debili N., Vainchenker W., Giraudier S.
Spontaneous growth of megakaryocyte progenitors is one of the biologic hallmarks of idiopathic myelofibrosis (IMF). The molecular mechanisms underlying this hypersensitivity to cytokines are poorly understood. Using a differential display approach, we previously observed FK506 binding protein 51 (FKBP51) overexpression in pathologic megakaryocytes from IMF. Using an FKBP51-overexpressing cell line, we found sustained STAT5 activation associated with JAK2 phosphorylation. We subsequently tested whether this transcription factor was activated in patient samples. We detected a STAT5 nuclear translocation and activation in spontaneously grown megakaryocytes and in circulating CD34(+) cells from the majority of patients studied. The biologic role of this JAK/STAT pathway activation was demonstrated by inhibiting both the anti-apoptotic phenotype mediated by FKBP51 overexpression in UT7 cells and the spontaneous megakaryocytic growth by addition in culture of the JAK2 inhibitor AG490 or overexpression of a STAT5b dominant negative or SOCS-1. These results demonstrate that a constitutive STAT5 activation in IMF is indispensable for spontaneous growth of megakaryocytes. They also suggest that FKBP51 overexpression could be involved in STAT5 activation in IMF cells and in subsequent abnormal growth.