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Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome.

ABSTRACT: Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.

SUBMITTER: Laurent AP

PROVIDER: S-EPMC7387246 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome.

Laurent Anouchka P AP Kotecha Rishi S RS Malinge Sébastien S

Leukemia 20200520 8

Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor con ...[more]

PMID: 32433508

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Project description:Background Respiratory infectious complications remain a major cause of morbidity and mortality in children with hematological malignancies. Knowledge regarding the lung microbiome in aforementioned children is limited. Methods A prospective cohort was conducted, enrolling 16 children with hematological malignancies complicated with moderate-to-severe lower respiratory tract infections (LRTIs) versus 21 LRTI children with age, gender, weight, and infection severity matched, with no underlying malignancies, to evaluate the lung microbiome from bronchoalveolar lavage fluid samples in different groups. Results The lung microbiome from children with hematological malignancies and LRTIs showed obviously decreased α and β diversity; increased microbial function in infectious disease:bacteria/parasite; drug resistance:antimicrobial and human pathogenesis than the control group; a significantly reduced proportion of Firmicutes, Bacteroidota, Actinobacteriota; increased Proteobacteria at the phylum level; and distinctly elevated Parabacteroides, Klebsiella, Grimontia, Escherichia_Shigella, unclassified_Enterobacteriaceae at the genus level than the control group. Furthermore, it was revealed that α diversity (Shannon), β diversity (Bray–Curtis dissimilarity), Proteobacteria at the phylum level, and unclassified_Enterobacteriaceae and Escherichia_Shigella at the genus level were significantly negatively associated with hospitalization course whereas Firmicutes at the phylum level was established positively correlated with the hospitalization course. Conclusions Children with hematological malignancies and LRTIs showed obviously decreased α and β diversity, significantly increased function in infectious disease pathogenesis, antimicrobial drug resistance, and unfavorable environment tolerance. Moreover, α diversity (Shannon), β diversity (Bray–Curtis dissimilarity), and Proteobacteria may be used as negative correlated predictors for hospitalization course in these children whereas Firmicutes may be utilized as a positive correlated predictor.

Project description:Imipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population. After children were treated with imipenem-cilastatin (IMP-CS), blood samples were collected from the children and the concentrations of imipenem were quantified using high-performance liquid chromatography with UV detection. Then, a population-level pharmacokinetic analysis was conducted using NONMEM software. Data were collected from 56 children (age range, 2.03 to 11.82 years) with hematological malignancies to conduct a population pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be the most suitable. The parameters of current weight, age, and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1%, and 67.1% of the children reached the pharmacodynamic target (the percentage of the time during the total dosing interval that the free drug concentration remains above the MIC of 70%) against sensitive pathogens with an MIC of 0.5 mg/liter with imipenem at 15, 20, and 25 mg/kg of body weight every 6 h (q6h), respectively. However, only 11.1% of the children achieved the pharmacodynamic target against Pseudomonas aeruginosa isolates with an MIC of 2 mg/liter at a dose of 25 mg/kg q6h. The population pharmacokinetics of imipenem were assessed in children. The current dosage regimens of imipenem result in underdosing against resistant pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h. (The study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT03113344.).

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Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome.

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Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome.

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