Decreased expression of fetal hemoglobin around the time of birth represents the defining mechanism in the clinical manifestation of sickle-cell and beta-thalassemia syndromes. Therefore, prevention or reversal of that process represents a major clinical goal for the treatment of those diseases. An ongoing interest of the laboratory involves the study of signal transduction cascades and growth among fully committed erythroid cells as a method of increasing levels of fetal hemoglobin in adult humans. In this context, we developed a standard experimental assay of cultured human erythroid progenitor cells obtained from normal volunteers as well as patients with hemoglobinopathies to identify cytokines capable of modulating erythroid growth and fetal hemoglobin production during adult erythropoiesis. Stem cell factor (SCF) was identified as having significant effects upon erythroid growth and fetal hemoglobin production even among committed proerythroblasts. That approach led to the discovery that TGF-beta, SCF and Erythropoietin act in concert to increase fetal hemoglobin production. Those increases were pancellular, and resulted in production of HbF to levels that may be sufficient to reverse the sickle phenotype in vivo. Efforts have begun to determine the molecular mechanisms responsible for the cytokine effects and to correlate those findings in vivo using clinical samples from patients with hemoglobinopathies.

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de Vasconcellos, Jaira F; Tumburu, Laxminath; Byrnes, Colleen et al. (2017) IGF2BP1 overexpression causes fetal-like hemoglobin expression patterns in cultured human adult erythroblasts. Proc Natl Acad Sci U S A 114:E5664-E5672
de Vasconcellos, Jaira F; Byrnes, Colleen; Lee, Y Terry et al. (2017) Tough decoy targeting of predominant let-7 miRNA species in adult human hematopoietic cells. J Transl Med 15:169
de Vasconcellos, Jaira F; Lee, Y Terry; Byrnes, Colleen et al. (2016) HMGA2 Moderately Increases Fetal Hemoglobin Expression in Human Adult Erythroblasts. PLoS One 11:e0166928
Rabel, Antoinette; Leitman, Susan F; Miller, Jeffery L (2016) Ask about ice, then consider iron. J Am Assoc Nurse Pract 28:116-20
Krivega, Ivan; Byrnes, Colleen; de Vasconcellos, Jaira F et al. (2015) Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/?-globin looping. Blood 126:665-72
Lee, Y Terry; de Vasconcellos, Jaira F; Byrnes, Colleen et al. (2015) Erythroid-Specific Expression of LIN28A Is Sufficient for Robust Gamma-Globin Gene and Protein Expression in Adult Erythroblasts. PLoS One 10:e0144977
de Vasconcellos, Jaira F; Fasano, Ross M; Lee, Y Terry et al. (2014) LIN28A expression reduces sickling of cultured human erythrocytes. PLoS One 9:e106924
Lee, Y Terry; Kim, Ki Soon; Byrnes, Colleen et al. (2013) A synthetic model of human beta-thalassemia erythropoiesis using CD34+ cells from healthy adult donors. PLoS One 8:e68307
Lee, Y Terry; de Vasconcellos, Jaira F; Yuan, Joan et al. (2013) LIN28B-mediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo. Blood 122:1034-41
Meier, Emily Riehm; Byrnes, Colleen; Weissman, Maxine et al. (2011) Expression patterns of fetal hemoglobin in sickle cell erythrocytes are both patient- and treatment-specific during childhood. Pediatr Blood Cancer 56:103-9

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