Acquired mutations in  GATA1  in neonates with Down's syndrome with transient myeloid disorder

Groet, Jürgen; McElwaine, Suzanne; Spínelli, Mônica Glória Neumann; Rinaldi, Andrea; Burtscher, Ingo; Mulligan, Catherine; Mensah, Afua Adjeiwaa; Cavani, Simona; Dagna-Bricarelli, F; Basso, Giuseppe; Cotter, Finbarr E.; Nižetić, Dean

doi:10.1016/s0140-6736(03)13266-7

Cited by 159 publications

(129 citation statements)

References 5 publications

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“…[13][14][15][16][17][18][19] This suggests that trisomy 21 and GATA1 mutations cooperate to facilitate the development of AMkL in DS children. Overexpression of chromosome 21-localized transcription factor oncogenes including ERG, AML1 and ETS2 in DS may contribute to the megakaryocytic phenotype in DS leukemia cases.…”

Section: Overexpression Of Ets2 In Both Ds and Non-ds Megakaryoblastsmentioning

confidence: 98%

“…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%

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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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Section: Overexpression Of Ets2 In Both Ds and Non-ds Megakaryoblastsmentioning

confidence: 98%

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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“…The potential role of GATA-1 in hemopoietic malignancies is further supported by the observation that acquired mutations in GATA-1 have been associated with transient myeloid disorder in patients with Down's syndrome (36). However, the status of GATA-1 expression by hemopoietic cells in patients with MMM has been controversial.…”

Section: Gata-1 and MMMmentioning

confidence: 99%

Myelofibrosis with Myeloid Metaplasia: New Developments in Pathogenesis and Treatment

2004

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Myeloid metaplasia with myelofibrosis (MMM) is a chronic myeloproliferative disorder (CMPD) characterized by progressive anemia, massive splenomegaly, both hepatosplenic and non-hepatosplenic extramedullary hematopoiesis (EMH), a leukoerythroblastic blood smear, circulating progenitor cells, and marked bone marrow stromal reaction including collagen fibrosis, osteosclerosis and angiogenesis. The overall median survival is 5 years although it might range from 2 to 15 years depending on the presence or absence of clinically defined prognostic factors. Death is often due to leukemic transformation, portal hypertension or infection. In addition to shortened survival, quality of life is often affected by frequent red blood cell transfusions, profound constitutional symptoms, and cachexia. Drug therapy and autologous hematopoietic stem cell transplantation (HSCT) are of only palliative value and have not been shown to improve survival. The role of allogeneic HSCT, both myeloablative and non-myeloablative, is actively being investigated. Both splenectomy and radiation therapy have defined therapeutic roles to control EMH-associated symptoms. Analysis of the molecular biology of the disease is underway with the aid of animal models leading to the identification of novel therapeutic targets. Among the novel agents tested, thalidomide seems the most promising although newer agents are on the horizon.

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“…Van Esch et al (2000) identified mutations in GATA3 from kindreds notable for a rare and complex disease of hypoparathyroidism, sensorineural deafness and renal insufficiency (HDR syndrome/OMIM #146255). In addition, significant mutations in other members of the GATA family have been defined in other human diseases; for example, an acquired mutation in GATA1 results in megakaryoblastic leukemia in children with Down's syndrome (Wechsler et al, 2002;Groet et al, 2003), while germline mutations of human GATA4 have been associated with congenital heart defects (Garg et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Mutation of GATA3 in human breast tumors

et al. 2004

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GATA3 is an essential transcription factor that was first identified as a regulator of immune cell function. In recent microarray analyses of human breast tumors, both normal breast luminal epithelium and estrogen receptor (ESR1)-positive tumors showed high expression of GATA3. We sequenced genomic DNA from 111 breast tumors and three breast-tumor-derived cell lines and identified somatic mutations of GATA3 in five tumors and the MCF-7 cell line. These mutations cluster in the vicinity of the highly conserved second zinc-finger that is required for DNA binding. In addition to these five, we identified using cDNA sequencing a unique mis-splicing variant that caused a frameshift mutation. One of the somatic mutations we identified was identical to a germline GATA3 mutation reported in two kindreds with HDR syndrome/OMIM #146255, which is an autosomal dominant syndrome caused by the haplo-insufficiency of GATA3. The ectopic expression of GATA3 in human 293T cells caused the induction of 73 genes including six cytokeratins, and inhibited cell line doubling times. These data suggest that GATA3 is involved in growth control and the maintenance of the differentiated state in epithelial cells, and that GATA3 variants may contribute to tumorigenesis in ESR1-positive breast tumors.

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Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder

Cited by 159 publications

References 5 publications

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

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

Myelofibrosis with Myeloid Metaplasia: New Developments in Pathogenesis and Treatment

Mutation of GATA3 in human breast tumors

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