GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

Maroz, Aliaksandra; Stachorski, Lena; Emmrich, Stephan; Reinhardt, Katarina; Xu, Jian; Shao, Zongshu; Käbler, Sebastian; Dertmann, Tobias; Roberts, Irene; Vyas, Paresh; Juban, Gaëtan; Hennig, Christian; Hansen, Gesine; Li, Zhe; Orkin, Stuart H.; Reinhardt, Dirk; Klusmann, Jan‐Henning

doi:10.1038/leu.2013.373

Cited by 40 publications

(40 citation statements)

References 60 publications

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“…The typical morphologic features of blasts are similar to those of AMKL, but the morphology of TAM blasts is variable in practice. Increased neutrophils, myelocytes, monocytes, and basophils are frequently observed in peripheral blood smears, and, interestingly, there are cases of TAM involving prominent eosinophilia . Relatively small percentages of blasts are found in the bone marrow of patients with TAM .…”

Section: Clinical and Hematological Features Of Tammentioning

confidence: 99%

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Watanabe

2019

Pediatrics International

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Neonates with Down syndrome (DS) have a propensity to develop the unique myeloproliferative disorder, transient abnormal myelopoiesis (TAM). TAM usually resolves spontaneously in ≤3 months, but approximately 10% of patients with TAM die from hepatic or multi‐organ failure. After remission, 20% of patients with TAM develop acute myeloid leukemia associated with Down syndrome (ML‐DS). Blasts in both TAM and ML‐DS have trisomy 21 and GATA binding protein 1 (GATA1) mutations. Recent studies have shown that infants with DS and no clinical signs of TAM or increases in peripheral blood blasts can have minor clones carrying GATA1 mutations, referred to as silent TAM. Low‐dose cytarabine can improve the outcomes of patients with TAM and high white blood cell count. A number of studies using fetal liver cells, mouse models, or induced pluripotent stem cells have elucidated the roles of trisomy 21 and GATA1 mutations in the development of TAM. Next‐generation sequencing of TAM and ML‐DS patient samples identified additional mutations in genes involved in epigenetic regulation. Xenograft models of TAM demonstrate the genetic heterogeneity of TAM blasts and mimic the process of clonal selection and expansion of TAM clones that leads to ML‐DS. DNA methylation analysis suggests that epigenetic dysregulation may be involved in the progression from TAM to ML‐DS. Unraveling the mechanisms underlying leukemogenesis and identification of factors that predict progression to leukemia could assist in development of strategies to prevent progression to ML‐DS. Investigation of TAM, a unique pre‐leukemic condition, will continue to strongly influence basic and clinical research into the development of hematological malignancies.

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Section: Clinical and Hematological Features Of Tammentioning

confidence: 99%

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Watanabe

2019

Pediatrics International

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“…These results are especially encouraging, as some HDAC inhibitors are already US FDA approved (e.g., vorinostat) and more are currently in late-stage clinical trials/under review by the FDA (e.g., panobinostat). Similarly, it has been shown that BRD4 inhibition with JQ1 can decrease MYC expression and decrease GATA1s-induced hyperproliferation [80]. As more therapeutic options for targeting epigenetic processes emerge, they will likely present exciting new options for the treatment of ML-DS.…”

Section: Five-year Viewmentioning

confidence: 99%

Prognosis and management of acute myeloid leukemia in patients with Down syndrome

Caldwell

Taub²

2014

Expert Review of Hematology

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Children with Down syndrome (DS) are at a substantially increased risk to develop acute myeloid leukemia (AML). This increase in incidence is tempered, however, by favorable overall survival rates of approximately 80%, whereas survival for non-DS children with similar leukemic subtypes is <35%. In this review, the clinical studies that have contributed to this overall high survival will be presented and their individual successes will be discussed. Important issues including intensity of treatment regimens, the role of bone marrow transplants and prognostic indicators will be reviewed. In particular, the roles of high- vs low- vs very low-dose cytarabine will be discussed, as well as potential therapeutic options in the future and the direction of the field over the next 5 years. In summary, children with DS and AML should be treated with a moderate-intensity cytarabine-based regimen with curative intent.

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“…51 This defect was accompanied by impaired Myc gene repression and an expansion in eosinophils. Thus, the regulation of GATA1 chromatin binding and transcriptional activity is controlled by the N-terminus in multiple hematopoietic cells.…”

Section: A D E F B Cmentioning

confidence: 99%

Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression

et al. 2015

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GATA1 is a master transcriptional regulator of the differentiation of several related myeloid blood cell types, including erythrocytes and megakaryocytes. Germ-line mutations that cause loss of full length GATA1, but allow for expression of the short isoform (GATA1s), are associated with defective erythropoiesis in a subset of patients with Diamond Blackfan Anemia. Despite extensive studies of GATA1s in megakaryopoiesis, the mechanism by which GATA1s fails to support normal erythropoiesis is not understood. In this study, we used global gene expression and chromatin occupancy analysis to compare the transcriptional activity of GATA1s to GATA1. We discovered that compared to GATA1, GATA1s is less able to activate the erythroid gene expression program and terminal differentiation in cells with dual erythroid-megakaryocytic differentiation potential. Moreover, we found that GATA1s bound to many of its erythroid-specific target genes less efficiently than full length GATA1. These results suggest that the impaired ability of GATA1s to promote erythropoiesis in DBA may be caused by failure to occupy erythroid-specific gene regulatory elements. Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression ABSTRACT MethodsCell culture G1ME cells were maintained in 1% THPO-conditioned media or in media containing THPO, SCF and EPO, as described. 3 Retroviral transduction and constructsRetroviral supernatant was prepared and applied to cells, as previously described.32 MigR1 constructs containing HA-tagged GATA1 and GATA1s have been described previously.

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GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia

Cited by 40 publications

References 60 publications

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Prognosis and management of acute myeloid leukemia in patients with Down syndrome

Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression

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