Integrin ?6 mediates the drug resistance of acute lymphoblastic B-cell leukemia.

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 ?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 ?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 ?6-associated apoptosis using a conditional knockout model of ?6 in murine BCR-ABL1+ B-cell ALL cells and showed that ?6-deficient ALL cells underwent apoptosis. In vivo deletion of ?6 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 ?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 ?6 as a novel therapeutic target for ALL.

SUBMITTER: Gang EJ 

PROVIDER: S-EPMC7357190 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature