Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome

Greene, Mark E.; Mundschau, Gina; Wechsler, Joshua B.; McDevitt, Michael A.; Gamis, Alan S.; Karp, Judith E.; Gurbuxani, Sandeep; Arceci, Robert J.; Crispino, John D.

doi:10.1016/j.bcmd.2003.08.001

Cited by 84 publications

(55 citation statements)

References 25 publications

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“…18 Subsequently, GATA1 mutations were detected in the blasts of patients who have DS and TAM. 19,20 And, in sequential longitudinal samples from a single patient, megakaryoblasts detected first during TAM and subsequently during DS-AMKL were both found to harbor an identical GATA1 mutation. 16,21 Together, these findings and other corroborative reports indicate that TAM and DS-AMKL are indeed clonally related.…”

Section: Gata1 Mutations and Disease Pathogenesismentioning

confidence: 92%

Transient Abnormal Myelopoiesis in Neonates: GATA Get the Diagnosis

Bombery

Vergilio

2014

Archives of Pathology &Amp; Laboratory Medicine

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Transient abnormal myelopoiesis occurs exclusively in patients with Down syndrome (constitutional trisomy 21), manifests in the neonatal period, and is characterized by circulating megakaryoblasts with varied degrees of multisystem organ involvement. In most cases, this process resolves spontaneously by 3 to 6 months of age, but for some, the disease can be fatal. Affected patients are particularly prone to develop acute megakaryoblastic leukemia in early childhood. Somatic GATA1 mutations are believed to be pivotal in the development of transient abnormal myelopoiesis and have proven to be a marker of clonal identity in its evolution to megakaryoblastic leukemia. We describe a study case of transient abnormal myelopoiesis and review the clinical manifestations, laboratory features, natural history, molecular genetics, and postulated disease pathogenesis of this disorder.

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Section: Gata1 Mutations and Disease Pathogenesismentioning

confidence: 92%

Transient Abnormal Myelopoiesis in Neonates: GATA Get the Diagnosis

Bombery

Vergilio

2014

Archives of Pathology &Amp; Laboratory Medicine

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“…[14][15][16][17][18][19] More intriguingly, these mutations do not appear to play a role in non-DS AMKL, with the exception of one case of identical twins both with acquired trisomy 21 and GATA1 exon 2 mutations. 17 This suggests that the oncogenic function of an exon 2 mutation in GATA1 is dependent on trisomy 21. Mutations in the second exon of GATA1 prevent expression of the wild-type full-length isoform of the protein and result in the production of a shorter isoform, GATA1s.…”

Section: Introductionmentioning

confidence: 89%

Hematopoietic defects in the Ts1Cje mouse model of Down syndrome

Carmichael

Majewski

Alexander

et al. 2009

Blood

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Down syndrome (DS) persons are born with various hematopoietic abnormalities, ranging from relatively benign, such as neutrophilia and macrocytosis, to a more severe transient myeloproliferative disorder (TMD). In most cases, these abnormalities resolve in the first few months to years of life. However, sometimes the TMD represents a premalignant disease that develops into acute megakaryocytic leukemia (AMKL), usually in association with acquired GATA1 mutations. To gain insight into the mechanisms responsible for these abnormalities, we analyzed the hematopoietic development of the Ts1Cje mouse model of DS. Our analyses identified defects in mature blood cells, including macrocytosis and anemia, as well as abnormalities in fetal liver and bone marrow stem and progenitor cell function.Despite these defects, the Ts1Cje mice do not develop disease resembling either TMD or AMKL, and this was not altered by a loss of function allele of Gata1. Thus, loss of Gata1 and partial trisomy of chromosome 21 orthologs, when combined, do not appear to be sufficient to induce TMD or AMKL-like phenotypes in mice. (Blood. 2009;113:1929-1937 Introduction Down syndrome (DS) results from trisomy of chromosome 21 and is the most common and best-characterized chromosomal disorder in humans. The frequency of DS is approximately 1 in 700 to 800 live births. Affected persons display a wide variety of phenotypic and physiologic abnormalities, including mental retardation, facial dysmorphia, and cardiac anomalies. DS persons are also afflicted with a variety of hematopoietic defects encompassing all lineages of the hematopoietic system, including thrombocytopenia, neutrophilia, and macrocytosis. 1 These defects generally resolve in the first year or 2 of life; however, macrocytosis persists in approximately two-thirds of DS persons. 2 Approximately 10% of DS neonates are born with a transient myeloproliferative disease (TMD), which in most cases resolves within the first 3 months of life. TMD is characterized by uncontrolled proliferation of immature megakaryoblasts, which accumulate in the peripheral blood, fetal liver (FL), and bone marrow (BM). 3 It is thought to be a disorder of FL hematopoiesis because human fetuses, as young as 25 weeks, have been diagnosed with a congenital leukemia, suggestive of TMD. 4 The spontaneous remission of most DS TMD patients coincides with the transition from FL to BM hematopoiesis. 5,6 This suggests that the FL environment may be contributing to maintenance of the disease.In approximately 30% of DS TMD cases, the disorder represents a preleukemic disease that develops into acute megakaryocytic leukemia (AMKL). 7,8 This is a direct progression from TMD to AMKL, as the TMD blast cells cannot to be distinguished phenotypically from the AMKL blast cells of the same person. 9 The global transcriptional pattern of the 2 cell types is also remarkably similar, although they can be distinguished using hierarchical clustering. 10,11 In addition to a 500-fold increased risk of AMKL, DS persons also have a 20-fold ...

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“…By contrast, in the erythroid lineage Gata1 mRNA was produced at a level comparable with that in control mice because of employment of the alternative first exon IEb/c and newly identified IEd first exon. We found that mRNAs transcribed from these alternative first exons tend to produce variant GATA1 protein lacking the N-terminal domain, which is well observed in Down syndrome-related megakaryoblastic leukemia (15)(16)(17). Importantly, in mice with conditional knock-out of the entire Gata1 gene, erythroid progenitors underwent maturation arrest (4), whereas in IE-null mice we observed dyserythropoiesis with skewed erythroid maturation.…”

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confidence: 64%

Loss of the Gata1 Gene IE Exon Leads to Variant Transcript Expression and the Production of a GATA1 Protein Lacking the N-terminal Domain

Kobayashi

Shimizu

Kikuchi

et al. 2010

Journal of Biological Chemistry

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GATA1 is essential for the differentiation of erythroid cells and megakaryocytes. The Gata1 gene is composed of multiple untranslated first exons and five common coding exons. The erythroid first exon (IE exon) is important for Gata1 gene expression in hematopoietic lineages. Because previous IE exon knockdown analyses resulted in embryonic lethality, less is understood about the contribution of the IE exon to adult hematopoiesis. Here, we achieved specific deletion of the floxed IE exon in adulthood using an inducible Cre expression system. In this conditional knock-out mouse line, the Gata1 mRNA level was significantly down-regulated in the megakaryocyte lineage, resulting in thrombocytopenia with a marked proliferation of megakaryocytes. By contrast, in the erythroid lineage, Gata1 mRNA was expressed abundantly utilizing alternative first exons. Especially, the IEb/c and newly identified IEd exons were transcribed at a level comparable with that of the IE exon in control mice. Surprisingly, in the IE-null mouse, these transcripts failed to produce full-length GATA1 protein, but instead yielded GATA1 lacking the N-terminal domain inefficiently. With low level expression of the short form of GATA1, IE-null mice showed severe anemia with skewed erythroid maturation. Notably, the hematological phenotypes of adult IE-null mice substantially differ from those observed in mice harboring conditional ablation of the entire Gata1 gene. The present study demonstrates that the IE exon is instrumental to adult erythropoiesis by regulating the proper level of transcription and selecting the correct transcription start site of the Gata1 gene.

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Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome

Cited by 84 publications

References 25 publications

Transient Abnormal Myelopoiesis in Neonates: GATA Get the Diagnosis

Transient Abnormal Myelopoiesis in Neonates: GATA Get the Diagnosis

Hematopoietic defects in the Ts1Cje mouse model of Down syndrome

Loss of the Gata1 Gene IE Exon Leads to Variant Transcript Expression and the Production of a GATA1 Protein Lacking the N-terminal Domain

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