TY - JOUR
T1 - CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K-dependent manner
AU - Abdelouahab, Hadjer
AU - Zhang, Yanyan
AU - Wittner, Monika
AU - Oishi, Shinya
AU - Fujii, Nobutaka
AU - Besancenot, Rodolphe
AU - Plo, Isabelle
AU - Ribrag, Vincent
AU - Solary, Eric
AU - Vainchenker, William
AU - Barosi, Giovanni
AU - Louache, Fawzia
N1 - Publisher Copyright:
© Abdelouahab et al.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - JAK2 activation is the driver mechanism in BCR-ABL-negative myeloproliferative neoplasms (MPN). These diseases are characterized by an abnormal retention of hematopoietic stem cells within the bone marrow microenvironment and their increased trafficking to extramedullary sites. The CXCL12/CXCR4 axis plays a central role in hematopoietic stem cell/progenitor trafficking and retention in hematopoietic sites. The present study explores the crosstalk between JAK2 and CXCL12/CXCR4 signaling pathways in MPN. We show that JAK2, activated by either MPL-W515L expression or cytokine stimulation, cooperates with CXCL12/CXCR4 signaling to increase the chemotactic response of human cell lines and primary CD34+ cells through an increased phosphatidylinositol-3-kinase (PI3K) signaling. Accordingly, primary myelofibrosis (MF) patient cells demonstrate an increased CXCL12-induced chemotaxis when compared to controls. JAK2 inhibition by knock down or chemical inhibitors decreases this effect in MPL-W515L expressing cell lines and reduces the CXCL12/CXCR4 signaling in some patient primary cells. Taken together, these data indicate that CXCL12/CXCR4 pathway is overactivated in MF patients by oncogenic JAK2 that maintains high PI3K signaling over the threshold required for CXCR4 activation. These results suggest that inhibition of this crosstalk may contribute to the therapeutic effects of JAK2 inhibitors.
AB - JAK2 activation is the driver mechanism in BCR-ABL-negative myeloproliferative neoplasms (MPN). These diseases are characterized by an abnormal retention of hematopoietic stem cells within the bone marrow microenvironment and their increased trafficking to extramedullary sites. The CXCL12/CXCR4 axis plays a central role in hematopoietic stem cell/progenitor trafficking and retention in hematopoietic sites. The present study explores the crosstalk between JAK2 and CXCL12/CXCR4 signaling pathways in MPN. We show that JAK2, activated by either MPL-W515L expression or cytokine stimulation, cooperates with CXCL12/CXCR4 signaling to increase the chemotactic response of human cell lines and primary CD34+ cells through an increased phosphatidylinositol-3-kinase (PI3K) signaling. Accordingly, primary myelofibrosis (MF) patient cells demonstrate an increased CXCL12-induced chemotaxis when compared to controls. JAK2 inhibition by knock down or chemical inhibitors decreases this effect in MPL-W515L expressing cell lines and reduces the CXCL12/CXCR4 signaling in some patient primary cells. Taken together, these data indicate that CXCL12/CXCR4 pathway is overactivated in MF patients by oncogenic JAK2 that maintains high PI3K signaling over the threshold required for CXCR4 activation. These results suggest that inhibition of this crosstalk may contribute to the therapeutic effects of JAK2 inhibitors.
KW - CXCR4
KW - Hematopoiesis
KW - JAK2 inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85029116935&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10789
DO - 10.18632/oncotarget.10789
M3 - Article
C2 - 28903325
AN - SCOPUS:85029116935
SN - 1949-2553
VL - 8
SP - 54082
EP - 54095
JO - Oncotarget
JF - Oncotarget
IS - 33
ER -