Research Papers:

CXCR4- and BCR-triggered integrin activation in B-cell chronic lymphocytic leukemia cells depends on JAK2-activated Bruton's tyrosine kinase

Alessio Montresor, Lara Toffali, Antonella Rigo, Isacco Ferrarini, Fabrizio Vinante and Carlo Laudanna _

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Oncotarget. 2018; 9:35123-35140. https://doi.org/10.18632/oncotarget.26212

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Alessio Montresor1,2, Lara Toffali1,2, Antonella Rigo3, Isacco Ferrarini3, Fabrizio Vinante3 and Carlo Laudanna1,2

1Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona, Verona 37134, Italy

2The Center for Biomedical Computing (CBMC), University of Verona, Verona 37134, Italy

3Department of Medicine, Section of Hematology, Cancer Research & Cell Biology Laboratory, University of Verona, Verona 37134, Italy

Correspondence to:

Carlo Laudanna, email: [email protected]

Keywords: chronic lymphocytic leukemia; adhesion; chemokines; integrin activation; signal transduction

Received: July 18, 2018    Accepted: September 21, 2018    Published: October 12, 2018


Bruton’s tyrosine kinase (BTK) regulates the B-cell receptor (BCR) signaling pathway, which, in turn, plays a critical role in B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis. The BTK-specific inhibitor Ibrutinib blocks BCR signaling and is now approved as effective B-CLL therapy. Chemokines, such as the homeostatic chemokine CXCL12, play a central role in B-CLL pathogenesis and progression, by regulating CLL cell interaction with the stromal microenvironment, leading to cells survival and proliferation. In this study, we investigated, in normal versus CLL B-lymphocytes, the role of BTK in signal transduction activated by the CXCL12-CXCR4 signaling axis and its involvement in rapid integrin activation. We show that BTK is rapidly activated by CXCL12 in healthy as well as CLL B-lymphocytes, with a kinetic of tyr-phosphorylation coherent with rapid adhesion triggering. BTK inhibition prevents CXCL12-induced triggering of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) integrins. Furthermore, BTK inhibition blocks the activation of the small GTP-binding protein RhoA, controlling integrin affinity. Very importantly, we show that BTK tyr-phosphorylation and activation by CXCL12 depends on upstream activation of JAK2 tyrosine kinase. A comparative analysis of 36 B-CLL patients demonstrates that JAK2-dependent BTK regulatory role on integrin activation by CXCL12 is fully conserved in CLL cells. Finally, we show that the JAK2-BTK axis also regulates signaling to integrin activation by BCR. Thus, BTK and JAK protein tyrosine kinases (PTKs) manifest a hierarchical activity both in chemokine- as well as BCR-mediated integrin activation and dependent adhesion, potentially suggesting the possibility of combined therapeutic approaches to B-CLL treatment.

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