CD69 partially inhibits apoptosis and erythroid differentiation via CD24, and their knockdown increase imatinib sensitivity in BCR‐ABL‐positive cells

Abstract

Chronic myeloid leukemia (CML) is caused by a constitutively active BCR-ABL tyrosine kinase. Tyrosine kinase inhibitors (TKIs) imatinib and its derivatives represent a breakthrough for CML therapy, but the use of TKI alone is ineffective for many CML patients. CD69, an early activation marker of lymphocytes, participates in immune and inflammatory responses. Previous studies revealed that BCR-ABL upregulates CD69 expression; however, the role of CD69 in CML cells is unknown. Here, we demonstrate that BCR-ABL induced CD69 promoter activity and mRNA and protein expression via the NF-κB pathway. CD69 knockdown partially increased apoptosis and expression of erythroid differentiation markers, α-globin, ζ-globin, and glycophorin A, and increased imatinib sensitivity in K562 and KU812 CML cells. Gene microarray analysis and quantitative real-time PCR verified that CD24, an oncogenic gene, downregulated in K562 cells upon CD69 knockdown. CD69 overexpression increased, whereas CD69 knockdown inhibited CD24 promoter activity and mRNA and protein levels. CD24 knockdown also partially increased apoptosis, erythroid differentiation, and imatinib sensitivity in K562 cells, whereas its overexpression inhibited the effects of CD69 knockdown on apoptosis, erythroid differentiation, and imatinib sensitivity in K562 cells. Imatinib-induced apoptosis and erythroid differentiation were also inhibited by CD69 or CD24 overexpression in BCR-ABL-expressing CML cell lines and CD34 cells. Taken together, CD24 is a downstream effector of CD69. CD69 and CD24 partially inhibit apoptosis and erythroid differentiation in CML cells; thus, they may be potential targets to increase imatinib sensitivity.

Endothelial Cell Response in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

“…NF-κB regulates the transcription of many pro-inflammatory and pro-survival genes. We found nine upregulated pro-survival genes in MIS-C compared to KD, including S100A3 [51], TNFRSF4 [52], BIRC3 [53], WWC1 [54], VNN1 [55], CD69 [56], LTB [57], TRAF1 [58], and ANO9 [59]. We also found that an independent pro-apoptotic gene, IGFBP5 [60], was downregulated in MIS-C. Taken together, these findings suggest that ECs in MIS-C have a more pro-survival phenotype compared to KD.…”

8-Hydroxydaidzein, an Isoflavone from Fermented Soybean, Induces Autophagy, Apoptosis, Differentiation, and Degradation of Oncoprotein BCR-ABL in K562 Cells

“…CD69, a member of the calcium-dependent lectin superfamily of type II transmembrane receptors, was reported as the marker for BCR-ABL activity in chronic myeloid leukemia [67]. In addition, CD69 was found to inhibit the apoptosis and differentiation in K562 cells [68]. RT-Q-PCR in Figure 6b validated that 8-OHD (50 and 100 µM) inhibits CD69 mRNA expression after 48 h treatment.…”

IL-33 promotes anemia during chronic inflammation by inhibiting differentiation of erythroid progenitors

“…S5 A ). Among those genes down-regulated were several with known roles in erythroid differentiation, including vimentin ( Vim ) required for enucleation ( Xue et al, 1997 ) and the enzyme coproporphyrinogen III oxidase ( Cpox ) required for Hgb synthesis ( Taketani et al, 2001 ), whereas CD69, which inhibits erythroid differentiation ( Huang et al, 2018 ), was up-regulated ( Fig. 6 B and Fig.…”