Eva Szenes, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria
Andrea Härzschel, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Sarah Decker, Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
Erika Tissino, Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
Justine Pischeli, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria
Julia Christine Gutjahr, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria
Sandra Kissel, Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
Sandra Pennisi, Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
Jan Philip Höpner, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria
Alexander Egle, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria
Nadja Zaborsky, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria
Christine Dierks, Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
Marie Follo, Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
Alexandre Chigaev, Department of Pathology and Cancer Center, University of New Mexico, Albuquerque, NM, USA
Antonella Zucchetto, Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
Richard Greil, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria
Valter Gattei, Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
Tanja Nicole Hartmann, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Salzburg, Austria. tanjanhartmann@gmail.comDepartment of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany. tanjanhartmann@gmail.com

Document Type

Article

Publication Date

9-1-2020

Abstract

With the advent of small molecule inhibitors, sustained responses in chronic lymphocytic leukemia (CLL) patients have been achieved. Ibrutinib, an inhibitor of Bruton’s tyr- osine kinase (BTK), is a particularly potent treatment for CLL, with overall response rates of 82% in treatment-naive and 43% in relapsed-refractory patients [1]. These responses are accompanied by transient lymphocytosis in 50–70% of patients and a concomitant reduction of tumor burden in lymphoid organs [2]. We have recently demonstrated that the high-risk, CD49d-high CLL subgroup [3] displays reduced lymphocytosis and minor lymph node shrinkage upon ibru- tinib treatment [4]. CD49d is the alpha subunit of the integrin VLA-4, which plays an essential role in the tissue retention of cells, orchestrating their adhesion to stromal cells, e.g., follicular dendritic cells (fDCs), which in turn express the VLA-4 ligand VCAM-1. To facilitate this strong adhesion, VLA-4 needs to be activated [5]. We have demonstrated that in CLL the extended, high-affinity conformation of VLA-4 can be triggered by B cell receptor (BCR) stimulation [4]. Notably, upon treatment with ibrutinib, CD49d-high CLL cells maintain residual BCR-mediated inside-out activation of VLA-4, thus explaining the reduced clinical response of CD49d-expressing CLL [4]. Eμ-TCL1-transgenic (TCL1-tg) mice represent a widely used mouse model for CLL [6]. By using this model, here we found that: (i) murine leukemic cells express high levels of surface CD49d; (ii) the BCR-VLA-4 axis in TCL1-tg mice, as investigated upon BCR stimulation and/or expo- sure to BCR inhibitors, resembles that of the human CD49d-high CLL cohort; (iii) the in vivo distribution of TCL1-tg leukemic cells is dependent on VLA-4-mediated interactions with the microenvironment. Our data demon- strate the value of TCL1-tg mice as a model for CD49d- high CLL and corroborate the importance of retained BCR- induced VLA-4 activation in a clinical setting.

Download

Share

COinS