1. Activin A downregulates the CD69-MT2A axis via p38MAPK to induce erythroid differentiation that sensitizes BCR-ABL-positive cells to imatinib
- Author
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Chih-Wei Chen, Nai-Kuei Huang, Yueh-Lun Lee, Chia-Kwung Fan, Yen-Chou Chen, Chin-Wei Liu, and Huei-Mei Huang
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Fusion Proteins, bcr-abl ,Apoptosis ,Cell Differentiation ,Cell Biology ,p38 Mitogen-Activated Protein Kinases ,Activins ,Antigens, CD ,Drug Resistance, Neoplasm ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Imatinib Mesylate ,Humans ,Lectins, C-Type ,Metallothionein ,K562 Cells - 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
- Published
- 2021