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 Blood, 1 August 2006, Vol. 108, No. 3, pp. 1077-1083.
Prepublished online as a Blood First Edition Paper on April 13, 2006; DOI 10.1182/blood-2006-01-008912.

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RED CELLS

cMYB is involved in the regulation of fetal hemoglobin production in adults

Jie Jiang, Steve Best, Stephan Menzel, Nicholas Silver, Mei I. Lai, Gabriela L. Surdulescu, Tim D. Spector, and Swee Lay Thein

From the Molecular Haematology, Division of Gene and Cell Based Therapy, King's College London School of Medicine at King's College Hospital; the Twin Research and Epidemiology Unit, King's College London School of Medicine at St Thomas' Hospital; and the Department of Haematological Medicine, King's College Hospital, London, United Kingdom.

A quantitative trait locus (QTL) controlling HbF levels has previously been mapped to chromosome 6q23 in an Asian-Indian kindred with beta thalassemia and heterocellular hereditary persistence of fetal hemoglobin (HPFH). Five protein-coding genes, ALDH8A1, HBS1L, cMYB, AHI1, and PDE7B reside in this 1.5-megabase (Mb) candidate interval of 6q23. To direct sequencing efforts we compared the expression profiles of these 5 genes between 12 individuals with elevated and 14 individuals with normal HbF levels during adult erythropoiesis by real-time quantitative reverse transcription–polymerase chain reaction (RT-PCR). Two genes, cMYB and HBS1L, demonstrated simultaneous transcriptional down-regulation in individuals with elevated HbF levels. Transfection of K562 cells encoding human cDNA of cMYB and HBS1L genes showed that, although overexpression of ectopic cMYB inhibited {gamma}-globin gene expression, overexpression of HBS1L had no effect. Low levels of cMYB were associated with low cell expansions, accelerated erythroid maturation, and higher number of macrophages in erythroid cell culture. These observations suggest that differences in the intrinsic levels of cMYB may account for some of the variation in adult HbF levels. The possible mechanism of cMYB influencing {gamma}- to beta-globin switching is discussed.


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