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Sensitivity and Resistance to Therapy

The WHIM-like CXCR4S338X somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia

Leukemia volume 29, pages 169–176 (2015)Cite this article

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Abstract

CXCR4WHIM somatic mutations are common Waldenstrom’s Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis), CXCRS338X mutation in WM. Following SDF-1a stimulation, CXCR4S338X WM cells exhibited decreased receptor internalization, enhanced and sustained AKT kinase (AKT) and extracellular regulated kinase (ERK) signaling, decreased poly (ADP-ribose) polymerase and caspase 3 cleavage, and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4S338X-related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a-treated CXCR4S338X WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4WT cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a-treated CXCR4S338X WM cells demonstrating their role in SDF-1a-mediated ibrutinib resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4WHIM versus CXCR4WT WM patients, and remained active despite ibrutinib therapy in CXCR4WHIM patients. Last, CXCR4S338X WM cells showed varying levels of resistance to other WM relevant therapeutics, including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4WHIM mutations, and provide a framework for investigation of CXCR4 inhibitors in WM.

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Acknowledgements

This work is dedicated in memory of Dr Nicole Muller-Berat Killman, Editor in Chief of Leukemia, whose personal and caring nature, exemplary scientific aptitude and advancement of knowledge to benefit cancer patients through judicious peer review will be missed. The authors also acknowledge the generous support of the Peter and Helen Bing Foundation, the D’Amato Family Fund for Genomic Discovery, the Edward and Linda Nelson Fund for WM Research and the WM patients who provided their samples in support of these studies. Findings of this study were presented at the annual meeting of the American Society for Hematology in 2012 and 2013.

Author contributions

YC, ZRH and SPT conceived and designed the experiments, and wrote the manuscript. YC, ZRH and SPT performed the data analysis. LX, YC, XL, GY, NT and JC performed experiments. CJP, SK, JJC provided patient samples. SR performed immunohistochemistry studies.

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Authors and Affiliations

  1. Bing Center for Waldenstrom’s Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA, USA

    Y Cao, Z R Hunter, X Liu, L Xu, G Yang, J Chen, C J Patterson, N Tsakmaklis, S Kanan, J J Castillo & S P Treon

  2. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Y Cao, X Liu, G Yang, S Rodig, J J Castillo & S P Treon

  3. Department of Pathology, Boston University Medical School, Boston, MA, USA

    Z R Hunter

  4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    S Rodig

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Correspondence to S P Treon.

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Competing interests

SPT received research funding and consulting fees from Pharmacyclics Inc. and Janssen Pharmaceuticals Inc.

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Cao, Y., Hunter, Z., Liu, X. et al. The WHIM-like CXCR4S338X somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia. Leukemia 29, 169–176 (2015). https://doi.org/10.1038/leu.2014.187

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