Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression

Vip Viprakasit, Supachai Ekwattanakit, Suchada Riolueang, Nipon Chalaow, Chris Fisher, Karen Lower, Hitoshi Kanno, Kalaya Tachavanich, Sasithorn Bejrachandra, Jariya Saipin, Monthana Juntharaniyom, Kleebsabai Sanpakit, Voravarn Tanphaichitr, Duantida Songdej, Christian Babbs, Richard Gibbons, Sjaak Philipsen, Douglass Higgs

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    Abstract

    In this study, we report on 8 compound heterozygotes for mutations in the key erythroid transcription factor Krüppel-like factor 1 in patients who presented with severe, transfusion-dependent hemolytic anemia. In most cases, the red cells were hypochromic and microcytic, consistent with abnormalities in hemoglobin synthesis. In addition, in many cases, the red cells resembled those seen in patients with membrane defects or enzymopathies, known as chronic nonspherocytic hemolytic anemia (CNSHA). Analysis of RNA and protein in primary erythroid cells from these individuals provided evidence of abnormal globin synthesis, with persistent expression of fetal hemoglobin and, most remarkably, expression of large quantities of embryonic globins in postnatal life. The red cell membranes were abnormal, most notably expressing reduced amounts of CD44 and, consequently, manifesting the rare In(Lu) blood group. Finally, all tested patients showed abnormally low levels of the red cell enzyme pyruvate kinase, a known cause of CNSHA. These patients define a new type of severe, transfusion-dependent CNSHA caused by mutations in a trans-acting factor (Krüppel-like factor 1) and reveal an important pathway regulating embryonic globin gene expression in adult humans.

    Original languageEnglish
    Pages (from-to)1586-1595
    Number of pages10
    JournalBlood
    Volume123
    Issue number10
    DOIs
    Publication statusPublished - 2014

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  • Cite this

    Viprakasit, V., Ekwattanakit, S., Riolueang, S., Chalaow, N., Fisher, C., Lower, K., Kanno, H., Tachavanich, K., Bejrachandra, S., Saipin, J., Juntharaniyom, M., Sanpakit, K., Tanphaichitr, V., Songdej, D., Babbs, C., Gibbons, R., Philipsen, S., & Higgs, D. (2014). Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression. Blood, 123(10), 1586-1595. https://doi.org/10.1182/blood-2013-09-526087