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The marker chromosome revealed by conventional karyotyping at the age of 3 before pre-B-ALL developed is indicated by an arrow.
Source publication
Microdeletions and microduplications are recurrent in the q11.2 region of chromosome 22. The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from severe intellectual disability, facial dysmorphism, heart defects, and urogenital abnormalities to very mild symptoms. Both benign and malignant hematological entit...
Citations
... Хромосомная патология, как правило, сопровождается широким спектром клинических проявлений, которые во многом зависят от протяженности локуса хромосомного дисбаланса. Однако, независимо от вида анеуплоидии, а также размера делеции/дупликации, хромосомные болезни в большинстве случаев ассоциированы с повышенным риском развития ЗНО различных локализаций, включая гемобластозы [12][13][14][15] (табл. 1). ...
... и др. [12,15]. В практике врачей НИИ ДОиГ также встречались пациенты с гемобластозами в сочетании с микроделеционным синдромом. ...
Hematooncological diseases head the list in the structure of malignant neoplasms of childhood. Somatic mutations in tumor clone cells have been well studied, included in modern classifications, and are used to stratify patients into prognostic risk groups and select a therapy program. At the same time, more than 50 hereditary syndromes associated with the development of hemoblastoses have been described. Some of them (Down’s syndrome, Klinefelter’s syndrome, microdeletion syndromes et al.) are caused by chromosomal pathology, while others describe alterations of one or more genes with different types of inheritance and age of manifestation of hematooncological diseases. Genes of predisposition to hematooncological diseases are involved in the processes of DNA repair, regulation of the cell cycle, immune response and bone marrow function. This article presents current data on genetic syndromes associated with the development of hemoblastosis with a description of their own clinical observations.
... The fourth mitotic regulator was CDC45, which is required for DNA replication. Vaisvilas et al. [30] reported a patient with a de novo 6.6 Mb duplication in a chromosomal region containing the CDC45 gene, which resulted in pre-B ALL. They concluded that the overexpression of genes, such as CDC45, in the duplicated region responsible for the cell cycle, might have contributed to the formation of the leukemic clone in the bone marrow. ...
Mexico City has one of the highest incidences of acute lymphoblastic leukemia (ALL) globally, with patients showing low survival, and high relapse rates. To gain more insight into the molecular features of B-ALL in Mexican children, we isolated CD10 + /CD19 + precursor B lymphoblasts from four bone marrow and nine peripheral blood samples of B-ALL patients using a fluorescence-activated cell sorting protocol. The global gene expression profile (BM vs PB) revealed 136 differentially expressed genes; 62 were upregulated (45.6%) and 74 were downregulated (54.4%). Pearson’s correlation coefficient was calculated to determine the similarity between pre-B lymphoblast populations. We selected 26 highly significant genes and validated 21 by RT-qPCR ( CNN3, STON2, CALN1, RUNX2, GADD45A, CDC45, CDC20, PLK1, AIDA, HCK, LY86, GPR65, PIK3CG, LILRB2, IL7R, TCL1A, DOCK1, HIST1H3G, PTPN14, CD72, and NT5E ) . The gene set enrichment analysis of the total expression matrix and the ingenuity pathway analysis of the 136 differentially expressed genes showed that the cell cycle was altered in the bone marrow with four overexpressed genes ( PLK1, CDC20, CDC45, and GADD45A ) and a low expression of IL7R and PIK3CG, which are involved in B cell differentiation. A comparative bioinformatics analysis of 15 bone marrow and 10 peripheral blood samples from Hispanic B-ALL patients collected by the TARGET program, corroborated the genes observed, except for PIK3CG . We conclude the Mexican and the Hispanic B-ALL patients studied present common driver alterations and histotype-specific mutations that could facilitate risk stratification and diagnostic accuracy and serve as potential therapeutic targets.
... 13 Dysfunction of CDC45 results in 22q11.2 Deletion Syndrome (also known as DiGeorge Syndrome) [14][15][16][17][18] and Meier-Gorlin syndrome. [18][19][20][21] Patients with 22q11.2 ...
Objectives:
CDC45 is the core component of CMG (CDC45-MCMs-GINS) complex that plays important role in the initial step of DNA replication in eukaryotic cells. The expression level of cdc45 is under the critical control for the accurate cell cycle progression. Loss-of-function of cdc45 has been demonstrated to inhibit cell proliferation and leads to cell death due to the inhibition of DNA replication and G1-phase arrest. An increasing of CDC45 inhibits cell proliferation as well. Nevertheless, a systematic analysis of the effect of high dose of CDC45 on cell physiology and behaviors is unclear. In the present study, we aimed to investigate the effects and mechanisms of high dose of CDC45 on cell behaviors.
Materials and methods:
We overexpressed cdc45 in cultured cell lines, Ciona and Drosophila embryos, respectively. The cell cycle progression was examined by the BrdU incorporation experiment, flow cytometry and PH3 (phospho-Histone 3) staining. RNA-sequencing analysis and qRT-PCR were carried out to screen the affected genes in HeLa cells overexpressing cdc45. siRNA-mediated knockdown was performed to investigate gene functions in HeLa cells overexpressing cdc45.
Results:
We found that high level of cdc45 from different species (human, mammal, ascidian, and Drosophila) inhibited cell cycle in vitro and in vivo. High dose of CDC45 blocks cells entering into S phase. However, we failed to detect DNA damage and cell apoptosis. We identified hspa6 was the most upregulated gene in HeLa cells overexpressing cdc45 via RNA-seq analysis and qRT-PCR validation. Overexpression of Hs-hspa6 inhibited proliferation rate and DNA replication in HeLa cells, mimicking the phenotype of cdc45 overexpression. RNAi against hspa6 partially rescued the cell proliferation defect caused by high dose of CDC45.
Conclusions:
Our study suggests that high abundance of CDC45 stops cell cycle. Instead of inducing apoptosis, excessive CDC45 prevents cell entering S phase probably due to promoting hspa6 expression.
... deletion has been implicated in genomic diseases for long (Stachon et al., 2007). Chromosome duplications of the region in patients have been reported, establishing a new genomic duplication syndrome (Hoeffding et al., 2017;Li, Yi, et al., 2019;Portnoi, 2009;Vaisvilas et al., 2018) complementary to the 22q11.2 deletion syndrome. ...
Background
The aim of this study was to evaluate the application of BACs‐on‐Beads (BoBs™) assay for rapid detection of chromosomal abnormalities for prenatal diagnosis (PND).
Methods
A total of 1520 samples, including seven chorionic villi biopsy samples, 1328 amniotic fluid samples, and 185 umbilical cord samples from pregnant women were collected to detect the chromosomal abnormalities using BoBs™ assay and karyotyping. Furthermore, abnormal specimens were verified by chromosome microarray analysis (CMA) and fluorescence in situ hybridization (FISH).
Results
The results demonstrated that the success rate of karyotyping and BoBs™ assay in PND was 98.09% and 100%, respectively. BoBs™ assay was concordant with karyotyping for Trisomy 21, Trisomy 18, and Trisomy 13, sex chromosomal aneuploidy, Wolf–Hirschhorn syndrome, and mosaicism. BoBs™ assay also detected Smith–Magenis syndrome, Williams–Beuren syndrome, DiGeorge syndrome, Miller–Dieker syndrome, Prader–Willi syndrome, Xp22.31 microdeletions, 22q11.2, and 17p11.2 microduplications. However, karyotyping failed to show these chromosomal abnormalities. A case of 8q21.2q23.3 duplication which was found by karyotyping was not detected by BoBs™ assay. Furthermore, all these chromosomal abnormalities were consistent with CMA and FISH verifications. According to the reports, we estimated that the detection rates of karyotyping, BoBs™, and CMA in the present study were 4.28%, 4.93%, and 5%, respectively, which is consistent with the results of a previous study. The respective costs for the three methods were about $135–145, $270–290, and $540–580.
Conclusion
BoBs™ assay is considered a reliable, rapid test for use in PND. A variety of comprehensive technological applications can complement each other in PND, in order to maximize the diagnosis rate and reduce the occurrence of birth defects.
