The health burden from beta-hemoglobinopathies and thalassemias is enormous. Increased fetal hemoglobin(HbF) ameliorates the severity of these disorders. While much progress has been made in an understandingof the 'hemoglobin switch' from gamma- to beta-globin, specific intracellular regulators of this critical developmentalevent are unknown and the switch cannot be reliably manipulated in patients. This research is focused onnew approaches to the hemoglobin switch that rely on genetic, rather than strictly biochemical or molecular,strategies. Progress in several areas suggests that the time is propitious for new initiatives. Severalindependent, but complementary, approaches will be taken. First, integrative genomic analysis will beapplied to identify the specific locus at chromosome position Xp22 that has previously been linked to F-cellproduction by other investigators. Preliminary in silico analyses suggest a limited number of candidate geneswithin this interval. Candidates will be validated or excluded by association studies using high-density SNPs,sequencing of highly likely candidates, and functional studies in mouse erythroid cells harboring the humanbeta-globin locus.
The aim i s to identify the first trans-regulator of the hemoglobin switch. Second, high-levelHbF expression is a hallmark of the rare pediatric malignancy juvenile myeloid leukemia, a disorder thatarises sporadically or in the setting of Noonan's syndrome and neurofibromatosis type I. A common featureis mutation of PTPN11 or neurofibromin with consequent activation of the Ras pathway. Based on theseclinical observations, the hypothesis that increased Ras activity stimulates gamma-globin production will bepursued through the study of engineered mice that have been made available for these studies. If the Raspathway is validated as a modulator of HbF expression, this finding would open the way to consideration ofnew therapeutic approaches to influencing the hemoglobin switch in patients. In parallel, the potential role ofthe newly identified factor zfp148 in hemoglobin switching will be pursued in collaboration with Dr. Cantor(Project 4). Finally, unbiased genetic screens will be initiated to identify genes whose expression eitherpromotes or inhibits gamma-globin expression. An appropriate 'reporter' mouse erythroid cell line will be used inboth genome-wide siRNA and retroviral insertional mutagenesis screens. Through these multidisciplinaryapproaches unrecognized regulators of the hemoglobin switch will be discovered.
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