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Pediatric Oncology
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Stephen Lowis, Rachel Cox, John Moppett, Helen Rees
In addition there is a unique condition called transient myeloid leukemia of Down syndrome (TMLDS) that occurs in at least 10% of neonates with DS. This condition is characterized by an abnormal clonal proliferation of megakaryoblasts that resembles AML but spontaneously resolves. Some 30–40% of such patients will go on to develop megakaryoblastic AML within the next 3 years. Of note, mutations in the GATA-1 gene on the X chromosome (encoding for a transcription factor essential for normal erythroid and megakaryoblastic differentiation) are found exclusively in TAM and DS-AML M7. Such mutations have subsequently been discovered in blood samples from Guthrie cards of patients with M7 and their identical twins, making it highly likely that they are an example of the so-called “first hit” in the process of leukemogenesis.
Gene Expression Profiling to Detect New Treatment Targets in Leukemia and Lymphoma: A Future Perspective
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Torsten Haferlach, Wolfgang Kern, Alexander Kohlmann
Another approach was described by Qian et al. (21) in therapy-related AML and myeloid cell lines focussing on CD34-positive selected cells. They were the first ones to define a specific pattern of gene expression for t-AML in comparison with other AML subtypes. The most discriminating genes were found to be involved in arrested differentiation of early progenitor cells. A higher expression of cell cycle control genes such as CCNA2, CCNE2, and CDC2 and genes for cell cycle checkpoints such as BUB1 or growth (Myc) were found. Furthermore, downregulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, EKLF) and overexpression of FLT3 was detected. The authors concluded that these genes may be further investigated for new targets and drugs in this very unfavourable subtype of AML.
Embryonic and Fetal Erythropoiesis
Published in Stephen A. Feig, Melvin H. Freedman, Clinical Disorders and Experimental Models of Erythropoietic Failure, 2019
D. Wade Clapp, Kevin M. Shannon
GATA-1 transcription during fetal development and its mechanism of action have been studied recently. The GATA-1 gene is initially expressed during blood island formation but remains at low levels during murine embryonic erythropoiesis (days 8 to 11 of gestation).70 Despite relatively low mRNA levels, GATA-1 may be important in embryonic erythropoiesis. Gong et al.71 observed GATA-1 binding to discrete sites in the ε globin gene promoter. A site located 165 base pairs (bp) upstream (5′) of the ε gene has been conserved across mammalian species and is required for efficient in vitro expression of reporter plasmids in transfected cells.72 GATA-1 mRNA levels rise markedly in mouse liver at the beginning of definitive erythropoiesis (day 12); this coincides with the onset of high level β globin transcription.70
Two patients of trisomy 21 with transient abnormal myelopoiesis with hypereosinophilia without blasts in peripheral blood smears
Published in Pediatric Hematology and Oncology, 2020
Toshio Okamoto, Ken Nagaya, Tatsutoshi Sugiyama, Aiko Aoyama, Mitsumaro Nii, Hiroshi Azuma
In the present cases, GATA1 mutations were identified in polymorphonuclear leukocytes isolated from whole blood. As no circulating blasts were detected, the mutations were probably harbored in eosinophils. Additionally, we confirmed the absence of GATA1 mutation after recovery from TAM using peripheral blood leukocytes from case 2. In vitro, TAM blasts can differentiate into eosinophils harboring the same GATA1 mutation as TAM blasts.9,12 Therefore, we speculate that in the present cases, almost all of TAM blasts differentiated into eosinophils at the time of birth. Few reports are available regarding TAM with hypereosinophilia, and none of them describe patients without peripheral blasts and leukocytosis. Our report emphasizes that in neonates with Down syndrome and hypereosinophilia, TAM should be considered a differential diagnosis even in the absence of peripheral blasts. The presence of eosinophils with coarse eosinophilic cytoplasmic granules and, if available, abnormal WBC flow cytometry dot plot with left-shifted eosinophils may help diagnose TAM. The eosinophil counts of our patients spontaneously decreased by 2–3 weeks of age; thus, if TAM is suspected, genetic testing for GATA1 mutations should be performed early, before the eosinophil numbers normalize.
Transient leukemia of Down syndrome
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Valentina Sas, Cristina Blag, Gabriela Zaharie, Emil Puscas, Cosmin Lisencu, Nicolae Andronic-Gorcea, Sergiu Pasca, Bobe Petrushev, Irina Chis, Mirela Marian, Delia Dima, Patric Teodorescu, Sabina Iluta, Mihnea Zdrenghea, Ioana Berindan-Neagoe, Gheorghe Popa, Sorin Man, Anca Colita, Cristina Stefan, Seiji Kojima, Ciprian Tomuleasa
Missense mutations in GATA1 lead to congenital blood disorders (Figure 2). Starting from this idea, Wechsler et al. suggested that acquired mutations in GATA1 might be involved in the pathogenesis of other hematopoietic diseases [82]. They assessed leukemic cells from six patients and found that every individual with DS-AMkL contained mutations in GATA1 [82]. Each mutation results in the introduction of a premature stop codon in the gene sequence that encodes the amino-terminal activation domain. These mutations prevent the synthesis of full-length GATA1, but not the synthesis of a shorter variant that is initiated downstream. Short GATA1 (GATA1s) protein, which lacks the amino-terminal activation domain, binds DNA and interacts with its essential cofactor, friend of GATA1 (FOG1), to the same extent as does full-length GATA1, but has a reduced transactivation potential [82,83]. Splice mutants, which also result in the amino-terminal truncation of the GATA1 protein, have been found [84].
Molecular features, prognosis, and novel treatment options for pediatric acute megakaryoblastic leukemia
Published in Expert Review of Hematology, 2019
Federico De Marchi, Marito Araki, Norio Komatsu
As discussed, approximately 10% of DS children have TAM, a condition phenotypically indistinguishable from AMegL that usually self-resolves within three months of life (Figure 1). However, 20%–30% of DS TAM patients will develop AMegL. Analysis of 200 patients with DS by next-generation sequencing (NGS) revealed 29% of showed mutations in GATA1, and these mutations were found in virtually all patients with TAM and AMegL [14]. In TAM cases, GATA1 mutations are sufficient for condition development and disappear at disease remission (Figure 1). The GATA1 protein is expressed in erythroid, megakaryocytic, mast, and eosinophilic cells and is essential and necessary for normal erythropoiesis and megakaryocytic physiological development. Mutations in this gene are, therefore, associated with several hematological diseases [25]. GATA1 mutations in DS children create a stop codon in exon 2, generating a shorter mutant protein that binds the DNA but fails to initiate transcription [26]. Truncated GATA1 confers proliferative advantages to megakaryocytic cells, as shown in transgenic mouse models [27]. Mutant GATA1 is associated with regulatory elements of many activated and repressed genes, which may induce a differentiation blockade [28,29], when analyzed by chromatin immunoprecipitation sequencing (ChIP-seq) assay. In addition, self-renewal may be enhanced by epigenetic upregulation, as shown by microRNA miR-486-5p and dysregulation of miR-125b-2 [30,31] or by other still unknown mechanisms.