Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia
Year: 2020
Type: article
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.
Source: Blood
Authors: Eun Ji Gang, Hye Na Kim, Yao-Te Hsieh, Yongsheng Ruan, Heather A. Ogana, Solomon Lee, Jennifer Pham, Huimin Geng, Eugene Park, Lars Klemm, Cheryl L. Willman, William L. Carroll, Steven D. Mittelman, Etan Orgel, Matthew J. Oberley, Chintan Parekh, Hisham Abdel-Azim, Deepa Bhojwani, Alan S. Wayne, Adèle De Arcangelis, Elisabeth Georges-Labouesse, Elizabeth Wayner, Halvard Bonig, Aspram Minasyan, Johanna ten Hoeve, Thomas G. Graeber, Markus Müschen, Nora Heisterkamp, Yong-Mi Kim
Institutions: University of Southern California, Children's Hospital of Los Angeles, USC Norris Comprehensive Cancer Center, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, University of New Mexico, UNM Comprehensive Cancer Center, NYU Langone Health, New York University, University of California, Los Angeles, Centre National de la Recherche Scientifique, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, University of Washington, Fred Hutch Cancer Center, Goethe University Frankfurt, German Red Cross
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3013890633