1. Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia.
- Author
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Gang EJ, Kim HN, Hsieh YT, Ruan Y, Ogana HA, Lee S, Pham J, Geng H, Park E, Klemm L, Willman CL, Carroll WL, Mittelman SD, Orgel E, Oberley MJ, Parekh C, Abdel-Azim H, Bhojwani D, Wayne AS, De Arcangelis A, Georges-Labouesse E, Wayner E, Bonig H, Minasyan A, Ten Hoeve J, Graeber TG, Müschen M, Heisterkamp N, and Kim YM
- Subjects
- Animals, Antibodies, Neoplasm pharmacology, Antibodies, Neutralizing pharmacology, Apoptosis drug effects, Apoptosis genetics, Female, Humans, Male, Mice, Mice, Knockout, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Gene Deletion, Integrin alpha6 genetics, Integrin alpha6 metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Pyrimidines pharmacology
- 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., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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