Activin A downregulates the CD69-MT2A axis via p38MAPK to induce erythroid differentiation that sensitizes BCR-ABL-positive cells to imatinib.
Exp Cell Res
; 417(2): 113219, 2022 08 15.
Article
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| MEDLINE
| ID: mdl-35643179
ABSTRACT
Induction of differentiation sensitizes chronic myeloid leukemia (CML) cells to the BCR-ABL inhibitor imatinib by mechanisms that remain unknown. We previously identified the BCR-ABL downstream effector CD69 which inhibits imatinib-induced CML cell differentiation. Herein, we found that the erythroid differentiation inducers activin A and aclacinomycin A induced expression of erythroid markers (α-globin, ζ-globin, GATA-1, and glycophorin A) and simultaneously reduced CD69 levels in K562 CML cells. Blockade of p38MAPK by SB203580 and shRNA eliminated the inhibitory effect of activin A on the promoter, mRNA, and protein levels and positive cell population of CD69. CD69 overexpression inhibited activin A-induced erythroid marker expression. Pretreatment of K562 cells with activin A to induce differentiation followed by a subtoxic concentration of imatinib caused growth inhibition and apoptosis that was reduced by CD69 overexpression. Activin A also reduced the expression of CD69's potential downstream molecule metallothionein 2A (MT2A) via p38MAPK. MT2A-knockdown reduced CD69 inhibition of activin A-induced erythroid marker expression. Furthermore, MT2A-knockdown reduced CD69 inhibition of activin A-imatinib sequential treatment-mediated growth inhibition and apoptosis in K562 and BCR-ABL-expressing CD34+ cells. These results suggest that CD69 inhibits activin A induction of erythroid differentiation-mediated CML cell sensitivity to imatinib via MT2A. Therefore, activin A induction of erythroid differentiation sensitizes BCR-ABL-positive cells to imatinib by downregulating the erythroid differentiation suppressors CD69 and MT2A.
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Bases de datos:
MEDLINE
Asunto principal:
Leucemia Mielógena Crónica BCR-ABL Positiva
/
Proteínas Quinasas p38 Activadas por Mitógenos
Límite:
Humans
Idioma:
En
Revista:
Exp Cell Res
Año:
2022
Tipo del documento:
Article
País de afiliación:
Taiwán