Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib
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Ailin Guo1,*, Pin Lu1,*, Natalie Galanina2, Chadi Nabhan2, Sonali M. Smith2, Morton Coleman3, Y. Lynn Wang1
1Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago, Chicago, IL, USA
2Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
3Department of Medicine, Weill Cornell Medical College, New York, NY, USA
*These author contributed equally to this work
Y. Lynn Wang, e-mail: [email protected]
Keywords: BTK, ibrutinib, CLL proliferation, BCR pathway, IGHV mutational status
Received: June 27, 2015 Accepted: November 25, 2015 Published: December 22, 2015
In chronic lymphocytic leukemia (CLL), patients with unmutated immunoglobulin heavy chain variable region gene (UM-CLL) have worse outcomes than mutated CLL (M-CLL) following chemotherapy or chemoimmunotherapy. However, in the era of BCR-targeted therapies, the adverse prognostic impact of unmutated IGHV seems to be diminishing, and there are clinical datasets showing unexpected improved responses in UM-CLL. We investigated the biological differences of BTK activity between these subgroups and further compared the impact of ibrutinib on molecular and cellular behaviors. Immunoblotting analysis revealed that phosphorylated active BTK is significantly higher in UM-CLL. Moreover, UM-CLL, compared to M-CLL, displayed a much higher proliferative capacity that was correlated with higher phospho-BTK and greater sensitivity to ibrutinib. In addition, BTK depletion with siRNA led to a more prominent reduction in the proliferation of UM-CLL, suggesting that elevated BTK activity is responsible for increased cell proliferation. Further, cell signaling activity by multiple measurements was consistently higher in UM-CLL accompanied by a higher sensitivity to ibrutinib. These studies link UM-CLL to elevated BCR signaling, heightened BTK-dependent cell proliferation and increased sensitivity to ibrutinib. The prognostic significance of IGHV mutation should be reevaluated in the era of new therapies targeting BCR signaling.
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