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Induction of adult levels of beta-globin in human erythroid cells that intrinsically express embryonic or fetal globin by transduction with KLF1 and BCL11A-XL

Trakarnsanga, K. Wilson, M. C. Lau, W. Singleton, B. K. Parsons, S. F. Sakuntanaga, P. Kurita, R. Nakamura, Y. Anstee, D. J. Frayne, J.

HAEMATOLOGICA 2014. 99:1677-85
A major barrier to the clinical use of erythrocytes generated in vitro from pluripotent stem cells or cord blood progenitors is failure of these erythrocytes to express adult hemoglobin. The key regulators of globin switching KLF1 and BCL11A are absent or at a lower level than in adult cells in K562 and erythroid cells differentiated in vitro from induced pluripotent stem cells and cord blood progenitors. Transfection or transduction of K562 and cord blood erythroid cells with either KLF1 or BCL11A-XL had little effect on beta-globin expression. In contrast, transduction with both transcription factors stimulated beta-globin expression. Similarly, increasing the level of BCL11A-XL in the induced pluripotent stem cell-derived erythroid cell line HiDEP-1, which has levels of endogenous KLF1 similar to adult cells but lacks BCL11A, resulted in levels of beta-globin equivalent to that of adult erythroid cells. Interestingly, this increase in beta-globin was coincident with a decrease in epsilon- and zeta-, but not gamma-globin, implicating BCL11A in repression of embryonic globin expression. The data show that KLF1 and BCL11A-XL together are required, but sufficient to induce adult levels of beta-globin in induced pluripotent stem cell and cord blood-derived erythroid cells that intrinsically express embryonic or fetal globin.