Dual-specificity phosphatase 21 enhances the sensitivity of imatinib-resistant chronic myeloid leukemia cells to ponatinib through GATA-1-mediated erythroid differentiation.

BCR-ABL tyrosine kinase inhibitors (TKIs) effectively treat chronic myeloid leukemia (CML), but drug resistance remains a challenge. Inducing erythroid differentiation in CML cells to enhance their sensitivity to imatinib is a potential approach, but the key regulators are unclear. Imatinib-induced apoptosis and erythroid differentiation in CML cells are distinct processes, suggesting specific genes are involved in differentiation. Analysis of the Gene Expression Omnibus revealed that imatinib highly upregulated dual-specificity phosphatase 21 (DUSP21). A recent study showed that DUSP21 can inhibit cell proliferation. Since cell proliferation decreases during differentiation, we investigated DUSP21's role in CML cell differentiation and TKI sensitivity. Imatinib and ponatinib increased DUSP21 expression in imatinib-sensitive CML cells (K562 and BaF3/p210), whereas only ponatinib did so in imatinib-resistant cells (K562R and BaF3/T315I). DUSP21 overexpression promoted erythroid differentiation, reduced cell viability, and enhanced ponatinib-mediated growth inhibition and apoptosis in these cells. Furthermore, DUSP21 increased the expression of the erythroid transcription factor GATA-1 by activating its promoter. GATA-1 knockdown eliminated DUSP21's effects on erythroid differentiation and ponatinib sensitivity in K562 and K562R cells. Collectively, these findings suggest that DUSP21 acts as a positive regulator of erythroid differentiation in CML cells, and its overexpression sensitizes imatinib-resistant CML cells to ponatinib via GATA-1-mediated erythroid differentiation.