Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome

Taub, Jeffrey W.; Mundschau, Gina; Ge, Yubin; Poulik, Janet; Qureshi, Faisal; Jensen, Tanya L.; James, S. Jill; Matherly, Larry H.; Wechsler, Joshua B.; Crispino, John D.

doi:10.1182/blood-2004-04-1563

Cited by 97 publications

(71 citation statements)

References 9 publications

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“…3,28 TL likely arises from fetal liver hematopoietic progenitor cells after the acquisition of GATA1 mutations in the context of cellular trisomy 21. This hypothesis is supported by the detection of GATA1 mutations in DS fetal liver cells, 29 expanded numbers of megakaryocyte-erythroid progenitor cells during DS fetal hematopoiesis, 30 and the increased proliferative capacity conferred to murine fetal liver GATA1 mutations of all engrafted samples were shown to be concordant with those present in the primary human cell samples. c Primary sample; codon 13 of N-RAS (NC_000001.10; nucleotide 115258813-5).…”

Section: Discussionsupporting

confidence: 64%

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: Discussionsupporting

confidence: 64%

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

Doedens

et al. 2010

Leukemia

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“…GATA1 mutations are believed to represent early or initiating "genetic hits" in a multistep process of leukemogenesis in Down syndrome that can begin prenatally. 4 A new study from the Crispino lab in this issue of Blood continues to contribute to our understanding of the biology of leukemia in children with Down syndrome. Using the Ts65Dn strain of mice, which displays several of the classical features of Down syndrome, including heart defects, cognitive deficits, and craniofacial dysmorphology, Kirsammer and colleagues characterized hematopoiesis in the mice with a series of comprehensive studies.…”

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

confidence: 99%

Of mice and Down syndrome

Taub

2008

Blood

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“…A surprising twist in this story came with the discovery that a gene on chromosome X, GATA1, was mutated in the megakaryoblasts from all the patients with DS and either TMD or AMKL [6,7]. The mutations were also found in fetal liver of aborted DS fetuses [8]. The mutations are acquired as they are not found in remission samples, and are specific to the megakaryoblastic disorders associated with trisomy 21.…”

Section: Aneuploidy Of Chromosome 21 and Acute Megakaryocytic Leukemiamentioning

confidence: 99%

Trisomy of chromosome 21 in leukemogenesis

Izraeli

Rainis

Hertzberg

et al. 2007

Blood Cells, Molecules, and Diseases

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Extra copies of chromosome 21 are often found in sporadic leukemias. Constitutional trisomy 21 of Down syndrome (DS) is associated with markedly increased risk for childhood leukemia. Thus the oncogenic role of trisomy 21 in the more common sporadic childhood leukemias may be revealed through the investigations of the relatively rare leukemias of DS. Recent studies of the megakaryoblastic leukemias of Down syndrome have uncovered a developmental leukemogenic mechanism characterized by a unique pre-natal collaboration between overexpressed genes from chromosome 21 and an acquired mutation in the transcription factor GATA1. The base of the markedly enhanced risk for acute lymphoblastic leukemia conferred by trisomy 21 is still unclear. Studies of the leukemias of DS are likely to contribute to the general understanding of the oncogenic mechanisms of chromosomal aneuploidies, the most common abnormalities in cancer.

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Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome

Cited by 97 publications

References 9 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

Of mice and Down syndrome

Trisomy of chromosome 21 in leukemogenesis

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