Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia

Goemans, Bianca F.; Noort, Sanne; Blink, Marjolein; Wang, Yongdong; Peters, Susan T.C.J.M.; Wouwe, J.P. van; Kaspers, Gertjan J. L.; Haas, Valérie de; Kollen, Wouter J.W.; Velden, Vincent H.J. van der; Grüber, Tanja A.; Zwaan, C. Michel

doi:10.1038/s41375-021-01128-1

Cited by 14 publications

(10 citation statements)

References 12 publications

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“…Our functional analysis also indicated its involvement in apoptosis. The role of Gata1 in deregulation of hematopoiesis has been well established (Sportoletti et al, 2019;Goemans et al, 2021), whereas, the role of Foxo1 in hematopoiesis has only been recently reported (Gurnari et al, 2019;Zheng et al, 2020). Our results revealed the association of Foxo1 with several signaling pathways, cellular response to oxidative stress, insulin stimulus and carbohydrate metabolism.…”

Section: Discussionsupporting

confidence: 51%

Weighted gene co-expression network analysis identifies key hub genes and pathways in acute myeloid leukemia

Wang

Bajpai²,

Gu³

et al. 2023

Front. Genet.

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Introduction: Acute myeloid leukemia (AML) is the most common type of leukemia in adults. However, there is a gap in understanding the molecular basis of the disease, partly because key genes associated with AML have not been extensively explored. In the current study, we aimed to identify genes that have strong association with AML based on a cross-species integrative approach.Methods: We used Weighted Gene Co-Expression Network Analysis (WGCNA) to identify co-expressed gene modules significantly correlated with human AML, and further selected the genes exhibiting a significant difference in expression between AML and healthy mouse. Protein-protein interactions, transcription factors, gene function, genetic regulation, and coding sequence variants were integrated to identify key hub genes in AML.Results: The cross-species approach identified a total of 412 genes associated with both human and mouse AML. Enrichment analysis confirmed an association of these genes with hematopoietic and immune-related functions, phenotypes, processes, and pathways. Further, the integrated analysis approach identified a set of important module genes including Nfe2, Trim27, Mef2c, Ets1, Tal1, Foxo1, and Gata1 in AML. Six of these genes (except ETS1) showed significant differential expression between human AML and healthy samples in an independent microarray dataset. All of these genes are known to be involved in immune/hematopoietic functions, and in transcriptional regulation. In addition, Nfe2, Trim27, Mef2c, and Ets1 harbor coding sequence variants, whereas Nfe2 and Trim27 are cis-regulated, making them attractive candidates for validation. Furthermore, subtype-specific analysis of the hub genes in human AML indicated high expression of NFE2 across all the subtypes (M0 through M7) and enriched expression of ETS1, LEF1, GATA1, and TAL1 in M6 and M7 subtypes. A significant correlation between methylation status and expression level was observed for most of these genes in AML patients.Conclusion: Findings from the current study highlight the importance of our cross-species approach in the identification of multiple key candidate genes in AML, which can be further studied to explore their detailed role in leukemia/AML.

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Section: Discussionsupporting

confidence: 51%

Weighted gene co-expression network analysis identifies key hub genes and pathways in acute myeloid leukemia

Wang

Bajpai²,

Gu³

et al. 2023

Front. Genet.

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“…Mutations in this hematopoietic transcription factor result in a truncated protein which is believed to cooperate with trisomy 21 to drive the development of ML-DS [23]. Studies using highly sensitive GATA1 detection methods have been published, emphasizing the importance of GATA1 detection in MP-DS, including the application of advanced neonatal screening to identify neonates at risk for myeloid leukemia development [24, 25]. In fact, studies have investigated various levels of sensitivity in GATA1 mutation detection, where higher sensitivity combination methods of Sanger screening followed by NGS were deemed superior in identifying the actual incidence of GATA1 mutations in ML-DS [24].…”

Section: Discussionmentioning

confidence: 99%

“…GATA1 mutations have been documented in ∼3.8–59% of neonates with DS [4, 16, 17]. Particularly in TAM, GATA1 mutations have been detected in 10–15% of cases, where variation in blast percentage cutoffs constitute the TAM diagnosis [5, 11, 25]. In contrast, GATA1 mutations appear more frequent in ML-DS and have been detected in 56–90% of cases [24].…”

Section: Discussionmentioning

confidence: 99%

Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions

Akker¹,

Liu²,

Liu³

et al. 2023

Pathobiology

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Objectives: The incidence of myelodysplastic syndrome and acute myeloid leukemia is significantly increased in children with Down syndrome (DS). Within the revised 2016 WHO edition, these entities are jointly classified as myeloid leukemia associated with DS (ML-DS). Additionally, infants with DS may develop transient abnormal myelopoiesis (TAM) which is histomorphologically identical to ML-DS. While TAM is self-limiting, it is associated with an increased risk of subsequently developing ML-DS. Differentiating TAM and ML-DS is challenging but clinically critical. Methods: We performed a retrospective review of ML-DS and TAM cases collected from five large academic institutions in the United States. We assessed clinical, pathologic, immunophenotypic, and molecular features to identify differentiating criteria. Results: Forty cases were identified; 28 ML-DS and 12 TAM. Several features were diagnostically distinct, including younger age in TAM (p<0.05), as well as presentation with clinically significant anemia and thrombocytopenia in ML-DS (p<0.001). Dyserythropoeisis and dysmegakaryopoiesis were unique to ML-DS, as well as structural cytogenetic abnormalities aside from the constitutional trisomy 21. Immunophenotypic characteristics of TAM and ML-DS were indistinguishable, including the aberrant expression of CD7 and CD56 by the neoplastic myeloid blasts. Conclusions: The findings of the study confirm marked biological similarities between TAM and ML-DS. At the same time several significant clinical, morphologic and genetic differences were observed between TAM and ML-DS. The clinical approach and the differential diagnosis between these entities are discussed in detail.

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“…9 S e h a d o c u m e n t a d o q u e l a p r e s e n c i a de una mutación en el gen GATA1 en el cromosoma X es un factor predisponente y hasta el 11 % de los recién nacidos con SD que presentan esta mutación desarrollarán leucemia megacariocítica. [10][11][12][13][14] Debido al rápido deterioro de la primera paciente, no fue posible la realización del estudio del gen GATA1.…”

Section: Discussionunclassified

Trastornos mieloproliferativos y leucemia en síndrome de Down. Presentación de dos casos clínicos en el período neonatal

Castro

Aristizábal

et al. 2022

Arch Argent Pediat

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Reporte de casos RESUMENEl síndrome de Down predispone a trastornos mieloproliferativos. Se estima que del 5 % al 30 % de los neonatos con esta condición desarrollarán mielopoyesis anormal transitoria. El tratamiento no está estandarizado; la exanguinotransfusión y la citarabina podrían ser efectivos. Se describen dos casos de pacientes con síndrome de Down, quienes durante el período neonatal presentaron leucemia mieloide aguda y mielopoyesis anormal transitoria, los tratamientos utilizados y sus desenlaces. Se considera que la sospecha y el diagnóstico temprano de esta entidad son factores determinantes en el pronóstico. Palabras clave: síndrome mieloproliferativo transitorio, síndrome de Down, leucemia, síndrome de lisis tumoral.

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Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia

Cited by 14 publications

References 12 publications

Weighted gene co-expression network analysis identifies key hub genes and pathways in acute myeloid leukemia

Weighted gene co-expression network analysis identifies key hub genes and pathways in acute myeloid leukemia

Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions

Trastornos mieloproliferativos y leucemia en síndrome de Down. Presentación de dos casos clínicos en el período neonatal

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