Research Papers:

CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K-dependent manner

Hadjer Abdelouahab, Yanyan Zhang, Monika Wittner, Shinya Oishi, Nobutaka Fujii, Rodolphe Besancenot, Isabelle Plo, Vincent Ribrag, Eric Solary, William Vainchenker, Giovanni Barosi and Fawzia Louache _

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Oncotarget. 2017; 8:54082-54095. https://doi.org/10.18632/oncotarget.10789

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Hadjer Abdelouahab1,2,3,4, Yanyan Zhang1,3,4, Monika Wittner1,3,4, Shinya Oishi6, Nobutaka Fujii6, Rodolphe Besancenot1,3,4, Isabelle Plo1,3,4,7,8, Vincent Ribrag1,3,4, Eric Solary1,3,4, William Vainchenker1,3,4,8, Giovanni Barosi5 and Fawzia Louache1,2,3,4

1INSERM, UMR 1170, Gustave Roussy, Villejuif, France

2University Paris Diderot, Paris, France

3University Paris-Sud 11, Villejuif, France

4Gustave Roussy, Villejuif, France

5Center for the Study of Myelofibrosis, Biotechnology Research Area, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy

6Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto, Japan

7Equipe labellisée Ligue Nationale contre le Cancer, UMR 1170, Institut Gustave Roussy, Villejuif, France

8Grex, Laboratoire d’Excellence, Paris, France

Correspondence to:

Fawzia Louache, email: [email protected]

Keywords: JAK2 inhibitors, CXCR4, hematopoiesis

Received: January 27, 2016    Accepted: June 17, 2016    Published: July 22, 2016


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.

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