Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome

Xu, Gang

doi:10.1182/blood-2003-02-0390

Cited by 196 publications

(163 citation statements)

References 36 publications

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“…1,2 Transient leukemia (TL), a spontaneously reversible accumulation of megakaryocytic blasts in the blood of 10% of newborns with DS, [3][4][5] represents a putative precursor of leukemia in this group. Somatic mutations of GATA1, present in both TL and DS-ML blasts, [6][7][8][9][10] likely function as the initiating 'first event.' 11,12 After the identification of initiating cells in numerous human leukemias, 13 differences during disease evolution are beginning to emerge.…”

Section: Introductionmentioning

confidence: 99%

Functional differences between myeloid leukemia-initiating and transient leukemia cells in Down's syndrome

Doedens

et al. 2010

Leukemia

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Children with constitutional trisomy 21 or Down's syndrome (DS) are predisposed to develop myeloid leukemia (ML) at a young age. DS-ML is frequently preceded by transient leukemia (TL), a spontaneously resolving accumulation of blasts during the newborn period. Somatic mutations of GATA1 in the blasts of TL and DS-ML likely function as an initiating event. We hypothesized that the phenotypic difference between TL and DS-ML is due to a divergent functional repertoire of the leukemia-initiating cells. Using an NOD/SCID model, we found that cells initiating DS-ML engrafted, disseminated to distant bone marrow sites, and propagated the leukemic clone in secondary recipients. In contrast, TL cells lacked the ability to expand and to migrate, but were able to persist in the recipient bone marrow. We found some evidence of genomic progression with 1 of 9 DS-ML samples and none of 11 TL samples harboring a mutation of N-RAS. The findings of this pilot study provide evidence for the functional impact of second events underlying the transformation of TL into DS-ML and a needed experimental tool for the functional testing of these promoting events.

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Section: Introductionmentioning

confidence: 99%

Functional differences between myeloid leukemia-initiating and transient leukemia cells in Down's syndrome

Doedens

et al. 2010

Leukemia

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“…11,12 Somatic mutations in exon 2 of the X-linked gene, GATA1, which encodes a zinc-finger transcription factor that is essential for normal erythroid and megakaryocytic differentiation, have been detected exclusively and almost uniformly in all DS AMkL cases, but not in non-DS AML or non-AMkL DS leukemia cases. [13][14][15][16][17][18][19] The net effect of the mutations is to introduce early stop codons that result in the synthesis of a shorter GATA1 (GATA1s, 40 kDa) protein translated from a downstream initiation site, distinguishable from the full-length 50-kDa GATA1 protein in its transactivation capacity. GATA1 mutations in DS are believed to cause accumulation of poorly differentiated megakaryocytic precursors.…”

Section: Introductionmentioning

confidence: 99%

The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy

LaFiura

Dombkowski

et al. 2007

Leukemia

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Acute myeloid leukemia (AML) in Down syndrome (DS) children has several unique features including a predominance of the acute megakaryocytic leukemia (AMkL) phenotype, higher event-free survivals compared to non-DS children using cytosine arabinoside (ara-C)/anthracycline-based protocols and a uniform presence of somatic mutations in the X-linked transcription factor gene, GATA1. Several chromosome 21-localized transcription factor oncogenes including ETS2 may contribute to the unique features of DS AMkL. ETS2 transcripts measured by real-time RT-PCR were 1.8-and 4.1-fold, respectively, higher in DS and non-DS megakaryoblasts than those in non-DS myeloblasts. In a doxycycline-inducible erythroleukemia cell line, K562pTet-on/ETS2, induction of ETS2 resulted in an erythroid to megakaryocytic phenotypic switch independent of GATA1 levels. Microarray analysis of doxycycline-induced and doxycycline-uninduced cells revealed an upregulation by ETS2 of cytokines (for example, interleukin 1 and CSF2) and transcription factors (for example, TAL1), which are key regulators of megakaryocytic differentiation. In the K562pTet-on/ ETS2 cells, ETS2 induction conferred differences in sensitivities to ara-C and daunorubicin, depending on GATA1 levels. These results suggest that ETS2 expression is linked to the biology of AMkL in both DS and non-DS children, and that ETS2 acts by regulating expression of hematopoietic lineage and transcription factor genes involved in erythropoiesis and megakaryopoiesis, and in chemotherapy sensitivities.

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“…As little as 5% GATA-1 expression protects cells from apoptosis and induces leukemogenesis (36). In humans with Down syndrome, expression of a ''short'' GATA-1 (GATA-1s) lacking amino-terminal sequences is linked to a transient myeloproliferative disorder and acute megakaryoblastic leukemia (37)(38)(39). GATA-1s expression in megakaryoblast precursors deregulates genes that promote proliferation, which are normally repressed by GATA-1 (39,40).…”

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confidence: 99%

Differential sensitivities of transcription factor target genes underlie cell type-specific gene expression profiles

Johnson

Kim

Boyer

et al. 2007

Blood Cells, Molecules, and Diseases

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Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome

Cited by 196 publications

References 36 publications

Functional differences between myeloid leukemia-initiating and transient leukemia cells in Down's syndrome

Functional differences between myeloid leukemia-initiating and transient leukemia cells in Down's syndrome

The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy

Differential sensitivities of transcription factor target genes underlie cell type-specific gene expression profiles

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