Natural history of GATA1 mutations in Down syndrome

Ahmed, Momin; Sternberg, Alexander; Hall, Georgina; Thomas, Angela; Smith, Owen; O'Marcaigh, Aengus; Wynn, Robert F.; Stevens, Richard; Addison, M. Pule; King, Derek J.; Stewart, Barbara L.; Gibson, Brenda; Roberts, Irene; Vyas, Paresh

doi:10.1182/blood-2003-10-3383

Cited by 227 publications

(217 citation statements)

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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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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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“…GATA1 mutations disappear when TAM/ML-DS enters the remission phase, indicating that these are acquired events [35]. Although it is not yet clear when in fetal development GATA1 mutations arise, the earliest point at which mutations have been identified is 21 weeks of gestation [39].…”

Section: Gata1 Mutation Induces Tam In Ds Neonatesmentioning

confidence: 99%

“…Ahmed et al [35] reported that multiple separate GATA1 mutant clones could occur in an individual TAM patient. In addition, Xu et al [61] reported that ML-DS can arise from a minor TAM clone with a GATA1 mutation that is distinct from that of the patient's major TAM clone.…”

Section: Clinical Findingsmentioning

confidence: 99%

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Evolution of myeloid leukemia in children with Down syndrome

Saida

2016

Int J Hematol

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the general population, the distribution of malignancies is different [3]. Patients with DS show a unique spectrum of malignancies, with a 10-to 20-fold higher risk of acute leukemia and a lower incidence of solid tumors [3,4]. Death from malignancies other than leukemia is strikingly less common in patients of all ages in DS, and death from leukemia is more likely in children younger than 10 years of age with DS than in those without [5]. The most frequent form of leukemia during childhood, both with and without DS, is acute lymphoblastic leukemia (ALL), and the incidence of ALL in children with DS is approximately 20-fold higher than in non-DS children [3]. However, the most marked increase in incidence in DS infants is with acute megakaryoblastic leukemia (AMKL), a myeloid malignancy of platelet precursors. The relative risk of developing AMKL is estimated to be 500 times higher in children with DS than in the general population [6]. Unlike AMKL in non-DS patients, most AMKL associated with DS (DS-AMKL) patients usually respond well to chemotherapy.In most cases, DS-AMKL is preceded by a temporary form of megakaryoblastic leukemia unique to newborns with DS and known as transient abnormal myelopoiesis (TAM) or transient leukemia. TAM, a clonal myeloproliferative syndrome, presents in the fetus or a few days after birth and in most cases resolves spontaneously within 3 months [7,8]. Typically, TAM is characterized by the presence of high numbers of circulating blast cells expressing CD33, CD38, CD117, CD34, CD7, CD56, CD36, CD71, and CD42b [9], which are indistinguishable from blasts observed in DS-AMKL. More often, the clinical presentation of TAM varies from asymptomatic alterations in the blood count to disseminated leukemic infiltration. Clinically severe TAM (liver failure, pleural/pericardial effusion, ascites, renal failure, and coagulopathy) affects 10-30 % of patients with clinically diagnosed TAM, and Abstract Children with Down syndrome (DS) have a markedly increased risk of leukemia. They are at particular risk of acute megakaryoblastic leukemia, known as myeloid leukemia associated with DS (ML-DS), the development of which is closely linked to a preceding temporary form of neonatal leukemia called transient abnormal myelopoiesis (TAM). Findings from recent clinical and laboratory studies suggest that constitutional trisomy 21 and GATA1 mutation(s) cause TAM, and that additional genetic alteration(s) including those in epigenetic regulators and signaling molecules are involved in the progression from TAM to ML-DS. Thus, this disease progression represents an important model of multi-step leukemogenesis. The present review focuses on the evolutionary process of TAM to ML-DS, and advances in the understanding of perturbed hematopoiesis in DS with respect to GATA1 mutation and recent findings, including cooperating genetic events, are discussed.

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“…Infants with DS suffer from transient abnormal myelopoiesis (DS-TAM) at a high frequency, and approximately 20-30% of cases subsequently develop DS-related acute megakaryoblastic leukemia (DS-AMKL) [88][89][90]. Mutations in GATA1, encoding the megakaryocyte transcription factor, resulting in the production of N-terminal truncated GATA1 (GATA1s) is associated with DS-TAM and DS-AMKL [91][92][93]. The combination of GATA1 mutation(s) and constitutive Ts21 is the most likely cause of DS-TAM, and additional mutations are thought to result in DS-AMKL [94].…”

Section: In Vitro Models For Aneuploidy and Cancermentioning

confidence: 99%