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GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder.

ABSTRACT: Children with Down syndrome (DS) are at increased risk of developing distinctive clonal myeloid disorders, including transient abnormal myelopoiesis (TAM) and myeloid leukaemia of DS (ML-DS). TAM connotes a spontaneously resolving congenital myeloproliferative state observed in 10%-20% of DS newborns. Following varying intervals of apparent remission, a proportion of children with TAM progress to develop ML-DS in early childhood. Therefore, TAM and ML-DS represent a biological continuum. Both disorders are characterised by recurring truncating somatic mutations of the GATA1 gene, which are considered key pathogenetic events.We herein report, to our knowledge, the first observation on the frequency and nature of GATA1 gene mutations in a cohort of Malaysian children with DS-associated TAM (n = 9) and ML-DS (n = 24) encountered successively over a period of five years at a national referral centre.Of the 29 patients who underwent GATA1 analysis, GATA1 mutations were observed in 15 (51.7%) patients, including 6 (75.0%) out of 8 patients with TAM, and 9 (42.9%) of 21 patients with ML-DS. All identified mutations were located in exon 2 and the majority were sequence-terminating insertions or deletions (66.7%), including several hitherto unreported mutations (12 out of 15).The low frequency of GATA1 mutations in ML-DS patients is unusual and potentially indicates distinctive genomic events in our patient cohort.

SUBMITTER: Lum SH

PROVIDER: S-EPMC4971451 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder.

Lum Su Han SH Choong Soo Sin SS Krishnan Shekhar S Mohamed Zulqarnain Z Ariffin Hany H

Singapore medical journal 20160601 6

<h4>Introduction</h4>Children with Down syndrome (DS) are at increased risk of developing distinctive clonal myeloid disorders, including transient abnormal myelopoiesis (TAM) and myeloid leukaemia of DS (ML-DS). TAM connotes a spontaneously resolving congenital myeloproliferative state observed in 10%-20% of DS newborns. Following varying intervals of apparent remission, a proportion of children with TAM progress to develop ML-DS in early childhood. Therefore, TAM and ML-DS represent a biologic ...[more]

PMID: 27353457

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Project description:BackgroundLittle is known about body weight status and the association between body weight and common comorbidities in children and adults with Down syndrome (DS), autism spectrum disorder (ASD) and other intellectual and developmental disabilities (IDDs).MethodsData were extracted from the University of Kansas Medical Center's Healthcare Enterprise Repository for Ontological Narration clinical integrated data repository. Measures included demographics (sex, age and race), disability diagnosis, comorbid health conditions, height, weight and body mass index percentiles (BMI%ile; <18 years of age) or BMI (≥18 years of age).ResultsFour hundred and sixty-eight individuals with DS (122 children and 346 adults), 1659 individuals with ASD (1073 children and 585 adults) and 604 individuals with other IDDs (152 children and 452 adults) were identified. A total of 47.0% (DS), 41.9% (ASD) and 33.5% (IDD) of children had overweight/obese (OW/OB), respectively. Children with DS were more likely to have OW/OB compared with children with IDD or ASD [odds ratio (OR) = 1.91, 95% confidence interval (CI): (1.49, 2.46); OR = 1.43, 95% CI: (1.19, 1.72)], respectively. A total of 81.1% (DS), 62.1% (ASD), and 62.4% (IDD) of adults were OW/OB, respectively. Adults with DS were more likely to have OW/OB compared with those with IDD [OR = 2.56, 95% CI: (2.16, 3.02)]. No significant differences were observed by race. In children with ASD, higher OW/OB was associated with significantly higher (compared with non-OW/OB) occurrence of sleep apnoea [OR = 2.94, 95% CI: (2.22, 3.89)], hypothyroidism [OR = 3.14, 95% CI: (2.17, 4.25)] and hypertension [OR = 4.11, 95% CI: (3.05, 5.54)]. In adults with DS, OW/OB was significantly associated with higher risk of sleep apnoea and type 2 diabetes [OR = 2.93, 95% CI: (2.10, 4.09); OR = 1.76, 95% CI: (1.11, 2.79) respectively]. Similarly, in adults with ASD and IDD, OW/OB was significantly associated with higher risk of sleep apnoea [OR = 3.39, 95% CI: (2.37, 4.85) and OR = 6.69, 95% CI: (4.43, 10.10)], type 2 diabetes [OR = 2.25, 95 % CI: (1.68, 3.01) and OR = 5.49, 95% CI: (3.96, 7.61)] and hypertension [OR = 3.55, 95% CI: (2.76, 4.57) and 3.97, 95% CI: (3.17, 4.97)].ConclusionFindings suggest higher rates of OW/OB in individuals with DS compared with ASD and IDD. Given the increased risk of comorbidities associated with the increased risk of OW/OB, identification of effective interventions for this special population of individuals is critical.

Project description:BackgroundChildren with Down syndrome (DS) have increased risk for developing AML (DS-AMKL), and they usually experience severe therapy-related toxicities compared to non DS-AMKL. Refractory/relapsed disease has very poor outcome, and patients would benefit from novel, less toxic, therapeutic strategies that overcome resistance. Relapse/resistance are linked to cancer stem cells with high aldehyde dehydrogenase (ALDH) activity. The purpose of the present work was to study less toxic alternative therapeutic agents for relapsed/refractory DS-AMKL.MethodsFourteen AML cell lines including the DS-AMKL CMY and CMK from relapsed/refractory AML were used. Cytarabine (Ara-C), bortezomib (BTZ), disulfiram/copper (DSF/Cu2+) were evaluated for cytotoxicity, depletion of ALDH-positive cells, and resistance. BTZ-resistant CMY and CMK variants were generated by continuous BTZ treatment. Cell viability was assessed using CellTiter-Glo®, ALDH activity by ALDELUORTM, and proteasome inhibition by western blot of ubiquitinated proteins and the Proteasome-Glo™ Chymotrypsin-Like (CT-like) assay, apoptosis by Annexin V Fluos/Propidium iodide staining, and mutations were detected using PCR, cloning and sequencing.ResultsAra-C-resistant AML cell lines were sensitive to BTZ and DSF/Cu2+. The Ara-C-resistant DS-AMKL CMY cells had a high percentage of ALDHbright "stem-like" populations that may underlie Ara-C resistance. One percent of these cells were still resistant to BTZ but sensitive to DSF/Cu2+. To understand the mechanism of BTZ resistance, BTZ resistant (CMY-BR) and (CMK-BR) were generated. A novel mutation PSMB5 Q62P underlied BTZ resistance, and was associated with an overexpression of the β5 proteasome subunit. BTZ-resistance conferred increased resistance to Ara-C due to G1 arrest in the CMY-BR cells, which protected the cells from S-phase damage by Ara-C. CMY-BR and CMK-BR cells were cross-resistant to CFZ and MG-132 but sensitive to DSF/Cu2+. In this setting, DSF/Cu2+ induced apoptosis and proteasome inhibition independent of CT-like activity inhibition.ConclusionsWe provide evidence that DSF/Cu2+ overcomes Ara-C and BTZ resistance in cell lines from DS-AMKL patients. A novel mutation underlying BTZ resistance was detected that may identify BTZ-resistant patients, who may not benefit from treatment with CFZ or Ara-C, but may be responsive to DSF/Cu2+. Our findings support the clinical development of DSF/Cu2+ as a less toxic efficacious treatment approach in patients with relapsed/refractory DS-AMKL.

Dataset Information

GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder.

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GATA1 mutations in a cohort of Malaysian children with Down syndrome-associated myeloid disorder.

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