Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia.
Animals
Antibodies, Neoplasm
/ pharmacology
Antibodies, Neutralizing
/ pharmacology
Apoptosis
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Deletion
Humans
Integrin alpha6
/ genetics
Male
Mice
Mice, Knockout
Neoplasm Proteins
/ antagonists & inhibitors
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
Pyrimidines
/ pharmacology
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
09 07 2020
09 07 2020
Historique:
received:
20
03
2019
accepted:
12
03
2020
pubmed:
29
3
2020
medline:
26
2
2021
entrez:
29
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32219444
pii: S0006-4971(20)61899-7
doi: 10.1182/blood.2019001417
pmc: PMC7357190
doi:
Substances chimiques
Antibodies, Neoplasm
0
Antibodies, Neutralizing
0
ITGA6 protein, human
0
Integrin alpha6
0
Neoplasm Proteins
0
Pyrimidines
0
nilotinib
F41401512X
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
210-223Subventions
Organisme : NCI NIH HHS
ID : R01 CA172896
Pays : United States
Organisme : NIH HHS
ID : S10 OD016387
Pays : United States
Informations de copyright
© 2020 by The American Society of Hematology.
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