GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome

Hitzler, Johann; Cheung, Joseph; Li, Yue; Scherer, Stephen W.; Zipursky, Alvin

doi:10.1182/blood-2003-01-0013

Cited by 294 publications

(230 citation statements)

References 22 publications

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“…TL blasts contain extra copies of chromosome 21 and occasional additional karyotypic abnormalities. All TL blasts have various somatic mutations in the X linked gene GATA 1 that encodes a transcription factor for normal erythroid and megakaryocytic development [5].…”

Section: Discussionmentioning

confidence: 99%

Transient Leukaemia: Leukaemia or Leukaemoid? A Diagnostic Dilemma

Marwah

Modi

Gupta

et al. 2011

Indian J Hematol Blood Transfus

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We report a case of a newborn male who had mongoloid slant and was hypotonic at birth. Routine investigations revealed leucocytosis (WBC [ 70,000/ cmm) with 50% blasts in peripheral blood film. Marrow examination confirmed the excess of blasts. Karyotyping revealed 47, XY ? 21 chromosomes. Due to absence of clinical symptoms, the baby was kept on follow-up without treatment. Within 7 weeks, PBF and bone marrow findings returned to normal, and the child was diagnosed as having Transient leukaemia with Down syndrome.

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Section: Discussionmentioning

confidence: 99%

Transient Leukaemia: Leukaemia or Leukaemoid? A Diagnostic Dilemma

Marwah

Modi

Gupta

et al. 2011

Indian J Hematol Blood Transfus

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“…[1][2][3] Sequence alterations in the region encoding the N-terminal activation domain of GATA1 include insertions, deletions, missense, nonsense, and splice-site mutations at the exon 2/intron boundary, resulting in the synthesis of a short-form GATA1 (GATA1s; 40-kDa) protein that exhibits altered transactivation capacity compared with the 50-kDa wild-type protein. GATA1 mutations are believed to represent early or initiating "genetic hits" in a multistep process of leukemogenesis in Down syndrome that can begin prenatally.…”

Section: Of Mice and Down Syndrome ----------------------------------mentioning

confidence: 99%

Of mice and Down syndrome

Taub

2008

Blood

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“…Estimates of the risk of ML-DS following TAM vary from ~5 % in the recent prospective study to 30 % in retrospective studies of clinically diagnosed TAM [8,11,40], and analysis of paired samples from the same patient found the identical GATA1 mutation in both pre-leukemic (TAM) and leukemic (ML-DS) stages [11,37,43].…”

Section: Additional Genomic Events Induce Ml-dsmentioning

confidence: 99%

“…However, most of the mutations are found in exon 2 of the GATA1 gene, with a minority in exon 3 or at the intronic boundary of exon 1 and 2, and lead to expression of N-terminally truncated GATA1 (GATA1s) protein [34,43]. GATA1s lacks the N-terminal transactivation domain, but retains both DNA-binding zinc fingers [34].…”

Section: Gata1 Mutation Induces Tam In Ds Neonatesmentioning

confidence: 99%

“…For example, recurrent additional cytogenetic abnormalities are commonly observed during disease progression [8,43,58,59]. Classically reported, the development of ML-DS is significantly correlated with karyotypic abnormalities such as dup(1q), del(6q), del(7p), dup(7q), +8, +11, and del(16q), which are rarely observed in the TAM phase [8,58,59].…”

Section: Additional Genomic Events Induce Ml-dsmentioning

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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GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome

Cited by 294 publications

References 22 publications

Transient Leukaemia: Leukaemia or Leukaemoid? A Diagnostic Dilemma

Transient Leukaemia: Leukaemia or Leukaemoid? A Diagnostic Dilemma

Of mice and Down syndrome

Evolution of myeloid leukemia in children with Down syndrome

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