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

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

doi:10.18632/oncotarget.10789

Abstract

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.

Highlights

BCR-ABL1 negative myeloproliferative neoplasms (MPN), i.e. Polycthemia Vera (PV), Essential Thrombo cythemia (ET) and Primary Mylofibrosis (PMF) are clonal disorders occurring in hematopoietic stem cells (HSC)
While normal HSC and progenitor cells (HSPC) proliferate and differentiate in the bone marrow microenvironment, patients with MPN are characterized by extramedullary hematopoiesis (EMH) that takes place in various sites with a marked prominence in the spleen. [12, 13] Recent data have documented the existence of MF HSC residing in the spleen with increased transplantation capacity in comparison to blood or marrow HSC [14]
MO7e-MPLW515L cells were selected for cytokine-independent growth and displayed constitutive STAT3, PI3K and extracellular signal-regulated kinase (ERK) phosphorylation that were reverted by the JAK2/JAK1 inhibitor AZD1480 (Figure 1A)

Summary

Introduction

BCR-ABL1 negative myeloproliferative neoplasms (MPN), i.e. Polycthemia Vera (PV), Essential Thrombo cythemia (ET) and Primary Mylofibrosis (PMF) are clonal disorders occurring in hematopoietic stem cells (HSC). All MPN driver mutations (JAK2V617F, MPLW515L/K, CALR mutations) activate the cytokine/ receptor JAK2 pathway and its downstream signaling such as the Signal transducer and activator of transcription www.impactjournals.com/oncotarget (STAT1, 3 and 5), phosphatidylinositol 3-kinase (PI3K)/ AKT/mTOR and the MAPK/ extracellular signal-regulated kinase (ERK) pathways. These mutations are responsible for myeloproliferation and can induce myelofibrosis (MF) in mouse models [3,4,5,6,7,8]. A recent study has shown that the MF splenic environment is characterized by an increased level of intact and functional CXCL12 that can contribute to the localization of MF CD34+ cells to the spleen [15]

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Results

Conclusion