Analysis of GATA1 mutations and leukemogenesis in newborns with Down syndrome

Queiroz, Lílian Barros; Lima, Beatriz Dolabela de; Mazzeu, Juliana Forte; Camargo, Ricardo; Córdoba, Mara Santos; Magalhães, Isis Quezado; Martins-de-Sa, C.; Ferrari, Íris

doi:10.4238/2013.october.18.1

Cited by 6 publications

(4 citation statements)

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“…Генетические события в бластных клетках при ТАМ [7]. По последним представлениям первым звеном в развитии ТАМ является наличие трисомии 21-й хромосомы в бластных клетках (первый «удар»).…”

Section: рисунокunclassified

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Cases of transient abnormal myelopoiesis

Klimentova

Чиквина

Хачатрян

2020

Voprosy gematologii/onkologii i immunopatologii v pediatrii

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Transient abnormal myelopoiesis (TAM) is a unique hematological syndrome specific for neonates with Down syndrome. Clinical and hematological manifestations of ТАМ are similar manifestations of acute leukemia, but they may resolve spontaneously by few weeks/months after birth. Summation trisomy 21 and GATA1 mutation in blast clone is a required element for development TAM. Presentation of this syndrome occurs in the first days of life; clinical manifestations may be absent (“silent” TAM) or even lead to death of fetus and neonate. The main interest in the study of this issue is the fact that after spontaneous regression there in 20% of cases at the age of 3–4 years developing acute megakaryoblastic leukaemia (AMKL). The basic transformation factors TAM to AMKL are unknown. In this article we represent 6 cases of TAM identified in Dmitry Rogachev National Research Center for Pediatric Hematology, Oncology, and Immunology from 2012 to 2019. Parents of these patients gave their agreement to use personal data in research and publications.

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“…Genetic events in blast cells in TAM [7]. According to the latest ideas, the first link in the development of TAM is the presence of trisomy 21 in blast cells (first "hit").…”

Section: Figurementioning

confidence: 99%

Cases of transient abnormal myelopoiesis

Klimentova

Чиквина

Хачатрян

2020

Voprosy gematologii/onkologii i immunopatologii v pediatrii

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“…In this context, based on the evidence that altered miRNA expression profiles are tumour-initiating events and a common hallmark of haematological malignancies [28], it has been hypothesized that HSA21complete or partial trisomy could promote over-expression of different miRNAs cooperating with GATA-1 S in the pathogenesis of AMKL. Interestingly, a link was found between a set of HSA21-encoded miRNAs (miR-99a, let-7c, miR-155, miR-125b-2) and leukaemogenesis [29][30][31]. Particularly, T21dependent miR-125b-2 over-expression was found to have synergistic effects with GATA-1 S to promote proliferation and self-renewal of fetal myeloid cells.…”

Section: Introductionmentioning

confidence: 99%

miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1 _S expression

Sessa,

Trombetti,

Bianco

et al. 2024

Open Biol.

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Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1 S ). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1 S , we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an in silico prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression. Expression studies in K562 cells revealed that miR-1202 directly targets GATA-1, negatively regulates its expression, impairs GATA-1 S production, reduces cell proliferation, and increases apoptosis sensitivity. Furthermore, data from TAM and myeloid leukaemia patients provided substantial support to our study by showing that miR-1202 down-modulation is accompanied by increased GATA-1 levels, with more marked effects on GATA-1 S . These findings indicate that miR-1202 acts as an anti-oncomiR in myeloid cells and may impact leukaemogenesis at least in part by down-modulating GATA-1 S levels.

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“…A transient myeloproliferative disorder with immature MK features (impaired maturation of MKs) is seen exclusively in fetuses and neonates with Down syndrome and GATA1 mutations indicating that thrombopoietin (TPO)-independent pathways may play a critical role in neonatal/fetal MK maturation [22, 24, 25]. …”

Section: Introductionmentioning

confidence: 99%

Identification of a potent small molecule capable of regulating polyploidization, megakaryocyte maturation, and platelet production

et al. 2016

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BackgroundMegakaryocytic cell maturation involves polyploidization, and megakaryocyte (MK) ploidy correlates with their maturation and platelet production. Retardation of MK maturation is closely associated with poor MK engraftment after cord blood transplantation and neonatal thrombocytopenia. Despite the high prevalence of thrombocytopenia in a range of setting that affect infants to adults, there are still very limited modalities of treatment.MethodsHuman CD34+ cells were isolated from cord blood or bone marrow samples acquired from consenting patients. Cells were cultured and induced using 616452 and compared to current drugs on the market such as rominplostim or TPO. Ploidy analysis was completed using propidium iodide staining and flow cytometry analysis. Animal studies consisted of transplanting human CD34+ cells into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice followed by daily injections of 15 mg/kg of 616452.ResultsWithin one week of culture, the chemical was able to induce polyploidization, the process required for megakaryocyte maturation with the accumulation of DNA content, to 64 N or greater to achieve a relative adult size. We observed fold increases as high as 200-fold in cells of 16 N or greater compared to un-induced cells with a dose-dependent manner. In addition, MK differentiated in the presence of 616452 demonstrated a more robust capacity of MK differentiation than that of MKs cultured with rominplostim used for adult idiopathic thrombocytopenic purpura (ITP) patients. In mice transplanted with human cord blood, 616452 strikingly enhanced MK reconstitution in the marrow and human peripheral platelet production. The molecular therapeutic actions for this chemical may be through TPO-independent pathways.ConclusionOur studies may have an important impact on our fundamental understanding of fetal MK biology, the clinical management of thrombocytopenic neonates and leukemic differentiation therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0358-y) contains supplementary material, which is available to authorized users.

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Analysis of GATA1 mutations and leukemogenesis in newborns with Down syndrome

Cited by 6 publications

References 15 publications

Cases of transient abnormal myelopoiesis

Cases of transient abnormal myelopoiesis

miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1 _S expression

Identification of a potent small molecule capable of regulating polyploidization, megakaryocyte maturation, and platelet production

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Analysis of GATA1 mutations and leukemogenesis in newborns with Down syndrome

Cited by 6 publications

References 15 publications

Cases of transient abnormal myelopoiesis

Cases of transient abnormal myelopoiesis

miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1 S expression

Identification of a potent small molecule capable of regulating polyploidization, megakaryocyte maturation, and platelet production

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miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1 _S expression