Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Eun Ji Gang, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Hye Na Kim, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Yao-Te Hsieh, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Yongsheng Ruan, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Heather A. Ogana, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Solomon Lee, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Jennifer Pham, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Huimin Geng, Department of Systems Biology, Beckman Research Institute at City of Hope, Duarte, CA.
Eugene Park, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA
Lars Klemm, Department of Systems Biology, Beckman Research Institute at City of Hope, Duarte, CA
Cheryl L. Willman, University of New Mexico Cancer Center and Departments of Pathology, Internal Medicine, Mathematics and Statistics, and Physics and Astronomy, University of New Mexico, Albuquerque, NM
William L. Carroll, Department of Pathology, New York University School of Medicine, New York, NY
Steven D. Mittelman, Division of Pediatric Endocrinology, University of California Los Angeles (UCLA) Children's Discovery and Innovation Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA.
Etan Orgel, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA
Matthew J. Oberley, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA
Chintan Parekh, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA
Hisham Abdel-Azim, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA
Deepa Bhojwani, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA
Alan S. Wayne, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA
Adèle De Arcangelis, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7104, INSERM U1258, Université de Strasbourg, Illkirch, France
Elisabeth Georges-Labouesse, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7104, INSERM U1258, Université de Strasbourg, Illkirch, France
Elizabeth Wayner, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA
Halvard Bonig, Goethe University School of Medicine, Institute for Transfusion Medicine and Immunohematology and German Red Cross Blood Service BaWuHe, Frankfurt, GermanyDepartment of Medicine/Hematology, University of Washington, Seattle, WA;
Aspram Minasyan, Department of Molecular and Medical Pharmacology, UCLA Metabolomics Center, UCLA, Los Angeles, CA
Johanna Ten Hoeve, Department of Molecular and Medical Pharmacology, UCLA Metabolomics Center, UCLA, Los Angeles, CA
Thomas G. Graeber, Department of Molecular and Medical Pharmacology, UCLA Metabolomics Center, UCLA, Los Angeles, CA
Markus Müschen, Department of Systems Biology, Beckman Research Institute at City of Hope, Duarte, CA.
Yong-Mi Kim, Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Nora Heisterkamp, Department of Systems Biology, Beckman Research Institute at City of Hope, Duarte, CA

Document Type

Article

Publication Date

7-9-2020

Abstract

Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

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