![]() Total RNA was extracted from white blood cells prepared by removal of erythrocytes by hypotonic buffer treatment of peripheral blood. 13 Genomic DNA was directly extracted from peripheral blood or bone marrow with the QIAamp blood mini kit (QIAGEN). The procedure for the detection of GATA1 mutations was described previously. The following laboratory data were obtained: a complete blood cell count at diagnosis including WBC and the percentage of blasts in the peripheral blood, coagulation parameters, liver enzymes (alanine aminotransferase and aspartate aminotransferase), and total bilirubin. ![]() ![]() The following clinical data were collected: sex, gestational age, birth weight, time of diagnosis, symptom at diagnosis, and clinical presentation. This study was approved by the Ethics Committee of Hirosaki University Graduate School of Medicine, and all clinical samples were obtained with informed consent from the parents of all patients with TAM, in accordance with the Declaration of Helsinki. 22 Nevertheless, the impact of a quantitative deficit of the factor on the pathogenesis of TAM and ML-DS has not been examined. 21 These observations indicate that the expression levels of GATA1 are crucial for the proper development of erythroid and megakaryocytic cells and compromised GATA1 expression is a causal factor in leukemia. 19, 20 Mice harboring a heterozygous GATA1 knockdown allele frequently develop erythroblastic leukemia. Reduced expression (or complete absence) of GATA1 in megakaryocytes leads to increased proliferation and deficient maturation as well as a reduced number of circulating platelets. ![]() The analysis of megakaryocyte-specific knockdown of GATA1 in vivo has revealed a critical role for this factor in megakaryocytic development. These findings strongly suggest that the qualitative deficit of GATA1 contributes to the genesis of TAM and ML-DS. 15–18 The mutations lead to exclusive expression of a truncated GATA1 protein (referred to as GATA1s) translated from the second methionine on exon 3. Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.īlast cells in most patients with TAM and ML-DS have mutations in exon 2 of the gene coding the transcription factor GATA1, 8–14 which is essential for normal development of erythroid and megakaryocytic cells. 001) and lower white blood cell counts ( P =. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS ( P <. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. We show here that the mutations affected the amount of mutant protein. To test whether the spectrum of transcripts derived from the mutant GATA1 genes affects the expression levels, we classified the mutations according to the types of transcripts, and investigated the modalities of expression by in vitro transfection experiments using GATA1 expression constructs harboring mutations. However, there are no reports on the expression levels of GATA1s in TAM blasts, and the risk factors for the progression to ML-DS are unidentified. Most cases of TAM carry somatic GATA1 mutations resulting in the exclusive expression of a truncated protein (GATA1s). Twenty percent to 30% of transient abnormal myelopoiesis (TAM) observed in newborns with Down syndrome (DS) develop myeloid leukemia of DS (ML-DS).
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