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

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 alpha 6 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 alpha 6-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 alpha 6-associated apoptosis using a conditional knockout model of alpha 6 in murine BCR-ABL1(+) B-cell ALL cells and showed that alpha 6-deficient ALL cells underwent apoptosis. In vivo deletion of alpha 6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in tyrosine eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that alpha 6 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 alpha 6 as a novel therapeutic target for ALL.