Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update

Bhatnagar, Neha; Nizery, Laure; Tunstall, Oliver; Vyas, Paresh; Roberts, Irene

doi:10.1007/s11899-016-0338-x

Cited by 127 publications

(170 citation statements)

References 57 publications

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“…After remission, approximately 20% of patients with TAM develop acute myeloid leukemia (AML) associated with Down syndrome (ML‐DS) . Given that blasts in both TAM and ML‐DS have common genetic abnormalities, including trisomy 21 and GATA binding protein 1 ( GATA1 ) mutation, TAM is considered a pre‐leukemic disorder, and understanding how TAM progresses to ML‐DS may provide information crucial to clarifying the mechanism involved in multi‐step leukemogenesis . Recent studies using a xenograft model and next‐generation sequencing (NGS) have detected subclones that emerge during the TAM phase and appear to expand to develop into overt leukemia through clonal selection and additional genetic alterations …”

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confidence: 99%

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Watanabe

2019

Pediatrics International

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Neonates with Down syndrome (DS) have a propensity to develop the unique myeloproliferative disorder, transient abnormal myelopoiesis (TAM). TAM usually resolves spontaneously in ≤3 months, but approximately 10% of patients with TAM die from hepatic or multi‐organ failure. After remission, 20% of patients with TAM develop acute myeloid leukemia associated with Down syndrome (ML‐DS). Blasts in both TAM and ML‐DS have trisomy 21 and GATA binding protein 1 (GATA1) mutations. Recent studies have shown that infants with DS and no clinical signs of TAM or increases in peripheral blood blasts can have minor clones carrying GATA1 mutations, referred to as silent TAM. Low‐dose cytarabine can improve the outcomes of patients with TAM and high white blood cell count. A number of studies using fetal liver cells, mouse models, or induced pluripotent stem cells have elucidated the roles of trisomy 21 and GATA1 mutations in the development of TAM. Next‐generation sequencing of TAM and ML‐DS patient samples identified additional mutations in genes involved in epigenetic regulation. Xenograft models of TAM demonstrate the genetic heterogeneity of TAM blasts and mimic the process of clonal selection and expansion of TAM clones that leads to ML‐DS. DNA methylation analysis suggests that epigenetic dysregulation may be involved in the progression from TAM to ML‐DS. Unraveling the mechanisms underlying leukemogenesis and identification of factors that predict progression to leukemia could assist in development of strategies to prevent progression to ML‐DS. Investigation of TAM, a unique pre‐leukemic condition, will continue to strongly influence basic and clinical research into the development of hematological malignancies.

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confidence: 99%

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Watanabe

2019

Pediatrics International

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“…A higher white blood cell count (>1 × 10 11 /L), ascites, hemorrhagic diathesis, early gestational age, and increased direct bilirubin levels have been reported to be independent risk factors for poor outcome [3]. It has been reported that a treatment with low-dose cytarabine, leukapheresis, exchange transfusion, or steroids has a beneficial effect on the outcome of TAM patients with risk factors for early death [5,6,8,14].…”

Section: Discussionmentioning

confidence: 99%

“…Infants with DS are at risk of developing transient abnormal myelopoiesis (TAM), which is characterized by the clonal proliferation of myeloid blasts with megakaryoblastic or erythroblastic features [2,3]. It presents in approximately 5-10% of neonates with DS [4], and most patients with TAM (>80%) obtain the spontaneous resolution of both clinical and laboratory abnormalities within 3 months after birth [5].…”

Section: Introductionmentioning

confidence: 99%

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Successful Liver Transplantation for Transient Abnormal Myelopoiesis-Associated Liver Failure

et al. 2017

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Infants with Down syndrome (DS) are at risk of developing a transient abnormal myelopoiesis (TAM). TAM occasionally involves liver fibrosis, which can be fatal. The management of liver disease in TAM has not yet been established and is mainly supportive. We report an infant with DS and TAM who developed end-stage liver failure. Liver dysfunction progressed even after blast cells disappeared from the circulation. He underwent a living-donor liver transplantation at 56 days of life without surgical complications. The explanted liver showed atrophy and severe fibrosis without leukemic cell infiltration. The posttransplant course was favorable with no hematological abnormality. He is doing well 8 months after transplantation. To the best of our knowledge, this report is the first showing that liver transplantation might be a treatment option for TAM-related liver failure.

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“…TAM is estimated to occur in 4-10% of neonates with DS (Zipursky 2003;Pine et al 2007). TAM is characterised by increased circulating blast cells that harbor acquired N-terminal truncating mutations in the key hematopoietic transcription factor gene GATA1 (Wechsler et al 2002;Groet et al 2003;Rainis et al 2003;Bhatnagar et al 2016). Furthermore, the interaction between DS, GATA1 mutations and TAM was reported, recently (Banno et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Cytokine Profiles in Pericardial Effusion in a Down Syndrome Infant with Transient Abnormal Myelopoiesis

Shitara

Takahashi

Aoki

et al. 2017

Tohoku J. Exp. Med.

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Infants with Down Syndrome (DS) are at risk of developing a transient abnormal myelopoiesis (TAM). TAM is characterised by increased circulating blast cells but usually self-limiting. DS patients with TAM sometimes show fetal hydrops and effusion in body cavities, but the mechanism remains unclear. We report here a case of infant with DS who had pericardial effusion, TAM, and eosinophilia. In her pericardial effusion, white blood cell count was 6.0 × 10 3 /µL, 41% of which were eosinophils. After administration of prednisolone, pericardial effusion gradually decreased, and TAM and eosinophilia improved. In order to elucidate the immunological mechanism, we measured the levels of 17 cytokines in her pericardial effusion fluid and serum. In her pericardial fluid, there were high levels of 12 cytokines, and they were higher than those in her serum. In particular, IL-6 (44,573 pg/mL), IL-8 (4,865 pg/mL), and IL-13 (579.41 pg/mL) were at extremely high levels in her pericardial fluid. After administration of prednisolone, the levels of 8 of the 12 elevated cytokines in her pericardial fluid decreased and all of the elevated cytokines decreased in her serum. Corticosteroids can be effective to reduce cytokine levels and the amount of effusion in patients with DS. It is presumed that effusion seen in DS with TAM could be related to an abnormal production of cytokines at the effusion site.

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Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update

Cited by 127 publications

References 57 publications

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Recent advances in the understanding of transient abnormal myelopoiesis in Down syndrome

Successful Liver Transplantation for Transient Abnormal Myelopoiesis-Associated Liver Failure

Cytokine Profiles in Pericardial Effusion in a Down Syndrome Infant with Transient Abnormal Myelopoiesis

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