scholarly journals ALLSorts: a RNA-Seq classifier for B-Cell Acute Lymphoblastic Leukemia.

2021 ◽  
Author(s):  
Breon M Schmidt ◽  
Lauren M Brown ◽  
Georgina L Ryland ◽  
Andrew Lonsdale ◽  
Hansen J Kosasih ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Learning Algorithm ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Supervised Machine Learning ◽  
World Health ◽  
Rna Seq ◽  
Cancer Subtypes ◽  
Cell Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Subtypes within B-ALL are distinguished by characteristic structural variants and mutations, which in some instances strongly correlate with responses to treatment. The World Health Organisation (WHO) recognises seven distinct classifications, or subtypes, as of 2016. However, recent studies have demonstrated that B-ALL can be segmented into 23 subtypes based on a combination of genomic features and gene expression profiles. A method to identify a patient's subtype would have clear clinical utility. Despite this, no publically available classification methods using RNA-Seq exist for this purpose. Here we present ALLSorts: a publicly available method that uses RNA-Seq data to classify B-ALL samples to 18 known subtypes and five meta-subtypes. ALLSorts is the result of a hierarchical supervised machine learning algorithm applied to a training set of 1223 B-ALL samples aggregated from multiple cohorts. Validation revealed that ALLSorts can accurately attribute samples to subtypes and can attribute multiple subtypes to a sample. Furthermore, when applied to both paediatric and adult cohorts, ALLSorts was able to classify previously undefined samples into subtypes. ALLSorts is available and documented on GitHub (https://github.com/Oshlack/AllSorts/).

scholarly journals Non-Coding RNA Signatures of B-Cell Acute Lymphoblastic Leukemia

2021 ◽  
Vol 22 (5) ◽  
pp. 2683
Author(s):  
Princess D. Rodriguez ◽  
Hana Paculova ◽  
Sophie Kogut ◽  
Jessica Heath ◽  
Hilde Schjerven ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Transcriptome Profiling ◽  
Rna Seq ◽  
Protein Coding ◽  
Non Coding Rna ◽  
Technological Developments ◽  
Cell Acute Lymphoblastic Leukemia

Non-coding RNAs (ncRNAs) comprise a diverse class of non-protein coding transcripts that regulate critical cellular processes associated with cancer. Advances in RNA-sequencing (RNA-Seq) have led to the characterization of non-coding RNA expression across different types of human cancers. Through comprehensive RNA-Seq profiling, a growing number of studies demonstrate that ncRNAs, including long non-coding RNA (lncRNAs) and microRNAs (miRNA), play central roles in progenitor B-cell acute lymphoblastic leukemia (B-ALL) pathogenesis. Furthermore, due to their central roles in cellular homeostasis and their potential as biomarkers, the study of ncRNAs continues to provide new insight into the molecular mechanisms of B-ALL. This article reviews the ncRNA signatures reported for all B-ALL subtypes, focusing on technological developments in transcriptome profiling and recently discovered examples of ncRNAs with biologic and therapeutic relevance in B-ALL.

scholarly journals Expression of ZNF695 Transcript Variants in Childhood B-Cell Acute Lymphoblastic Leukemia

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 716 ◽  
Author(s):  
Rosa ◽  
Villegas-Ruíz ◽  
Caballero-Palacios ◽  
Pérez-López ◽  
Murata ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Alternative Transcript ◽  
Human Transcriptome ◽  
Transcript Variants ◽  
Cell Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia is the most commonly diagnosed childhood malignancy worldwide; more than 50% of these cases are diagnosed in Mexico. Although the five-year survival rate is >80%, 30% of patients experience relapse with poor prognosis. Cancer-associated gene expression profiles have been identified in several malignancies, and some transcripts have been used to predict disease prognosis. The human transcriptome is incompletely elucidated; moreover, more than 80% of transcripts can be processed via alternative splicing (AS), which increases transcript and protein diversity. The human transcriptome is divided; coding RNA accounts for 2%, and the remaining 98% is noncoding RNA. Noncoding RNA can undergo AS, promoting the diversity of noncoding transcripts. We designed specific primers to amplify previously reported alternative transcript variants of ZNF695 and showed that six ZNF695 transcript variants are co-expressed in cancer cell lines. The amplicons were sequenced and identified. Additionally, we analyzed the expression of these six transcript variants in bone marrow from B-cell acute lymphoblastic leukemia patients and observed that ZNF695 transcript variants one and three were the predominant variants expressed in leukemia. Moreover, our results showed the co-expression of coding and long noncoding RNA. Finally, we observed that long noncoding RNA ZNF695 expression predicted survival rates.

Identifying IGH disease clones for MRD monitoring in childhood B-cell acute lymphoblastic leukemia using RNA-Seq

Leukemia ◽  
2020 ◽  
Vol 34 (9) ◽  
pp. 2418-2429 ◽  
Author(s):  
Zhenhua Li ◽  
Nan Jiang ◽  
Evelyn Huizi Lim ◽  
Winnie Hui Ni Chin ◽  
Yi Lu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Rna Seq ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Differential mRNA and long noncoding RNA expression profiles in pediatric B-cell acute lymphoblastic leukemia patients

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Jing Xia ◽  
Mengjie Wang ◽  
Yi Zhu ◽  
Chaozhi Bu ◽  
Tianyu Li
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Data Availability ◽  
Differentially Expressed ◽  
Kegg Analysis ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Background Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides (nt) that are involved in the pathogenesis and development of various cancers including B cell acute lymphoblastic leukemia (B–ALL). To determine the potential roles of lncRNAs involved in pathogenesis of B-ALL, we analyzed the expression profile of lncRNAs and mRNAs in B-ALL, respectively, and constructed lncRNAs/mRNAs interaction network. Methods We performed RNA sequencing of 10 non-leukemic blood disease donors and 10 B-ALL patients for Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Interactions among mRNAs were predicted using the STRING database. Quantitative real time PCR (qRT-PCR) was performed to verify the RNA-seq data of lncRNAs and mRNAs. Potential functions of subtype-specific lncRNAs were determined by using coexpression-based analysis on distally (trans-pattern) located protein-coding genes. Results A total of 1813 differentially expressed transcripts (DETs) and 2203 lncRNAs were identified. Moreover, 10 dysregulated lncRNAs and 10 mRNAs were randomly selected, and further assessed by RT-qPCR in vitro. Go and KEGG analysis demonstrated that the differentially expressed mRNAs were most closely associated with myeloid leukocyte activation and in transcriptional misregulation in cancer, respectively. In addition, co-expression analysis demonstrated that these lncRNAs, including MSTRG.27994.3, MSTRG.21740.1, ENST00000456341, MSTRG.14224.1 and MSTRG.20153.1, may mediate the pathogenesis and development of B-ALL via lncRNA-mRNA network interactions. Conclusions These results showed that several mRNAs and lncRNAs are aberrantly expressed in the bone marrow of B-ALL patients and play potential roles in B-ALL development, and be useful for diagnostic and/or prognostic purposes in pediatric B–ALL. Data availability The datasets used during our study are available through HARVARD Dataverse Persistent ID doi:10.7910/DVN/LK9T4Z.

scholarly journals RNA-sequencing analysis in B-cell acute lymphoblastic leukemia reveals aberrant gene expression and splicing alterations

2017 ◽  
Author(s):  
◽  
Olha Kholod
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Rna Sequencing ◽  
Lymphoblastic Leukemia ◽  
Statistical Testing ◽  
Rna Seq ◽  
Healthy Donors ◽  
Cell Acute Lymphoblastic Leukemia

Background: B-cell acute lymphoblastic leukemia (B-ALL) is a neoplasm of immature lymphoid progenitors and is the leading cause of cancer-related death in children. The majority of B-ALL cases are characterized by recurring structural chromosomal rearrangements that are crucial for triggering leukemogenesis, but do not explain all incidences of disease. Therefore, other molecular mechanisms, such as alternative splicing and epigenetic regulation may alter expression of transcripts that are associated with the development of B-ALL. To determine differentially expressed and spliced RNA transcripts in precursor B-cell acute lymphoblastic leukemia patients a high throughput RNA-seq analysis was performed. Methods: Eight B-ALL patients and eight healthy donors were analyzed by RNA-seq analysis. Statistical testing was performed in edgeR. Each annotated gene was mapped to its corresponding gene object in the Ingenuity KB. Analysis of RNA-seq data for splicing alterations in B-ALL patients and healthy donors was performed with custom Perl script. Results: Using edgeR analysis, 3877 DE genes between B-ALL patients and healthy donors based on TMM (trimmed mean of M-values) normalization method and false discovery rate, FDR less than 0.01, logarithmically transformed fold changes, logFC greater than 2) were identified. IPA revealed abnormal activation of ERBB2, TGFB1 and IL2 transcriptional factors that are crucial for maintaining proliferation and survival potential of leukemic 26 cells. B-ALL specific isoforms were observed for genes with roles in important canonical signaling pathways, such as oxidative phosphorylation and mitochondrial dysfunction. A mechanistic study with the Nalm 6 cell line revealed that some of these gene isoforms significantly change their expression upon 5-Aza treatment, suggesting that they may be epigenetically regulated in B-ALL. Conclusion: Our data provide new insights and perspectives on the regulation of the transcriptome in B-ALL. In addition, we identified transcript isoforms and pathways that may play key roles in the pathogenesis of B-ALL. These results further our understanding of the transcriptional regulation associated with B-ALL development and will contribute to the development of novel strategies aimed towards improving diagnosis and managing patients with B-ALL. Keywords: B-ALL, RNA-sequencing, differential gene expression, alternative splicing.

scholarly journals Novel Germline TRAF3IP3 Mutation in a Dyad with Familial Acute B Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Lauren Pommert ◽  
Robert Burns ◽  
Quinlan Furumo ◽  
Kirthi Pulakanti ◽  
Jon Brandt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Rna Seq ◽  
Structural Variant ◽  
Mutational Spectrum ◽  
Leukemia Development

Acute lymphoblastic leukemia (ALL) is the most common single malignancy in children, representing 25% of all new cancer diagnoses. Advances in genomic sequencing has demonstrated that inherited genetic risk factors play a larger role in leukemia development than previously appreciated. We identified a father-daughter dyad with childhood B cell acute lymphoblastic leukemia (B-ALL) and obtained their diagnostic bone marrow samples from the Children's Oncology Group (COG) bank in addition to germline samples via remission marrow (daughter) or buccal swab (father). Whole Exome Sequencing (WES) was performed and compared to a panel of normal to identify large genomic changes and single nucleotide variants. In parallel, RNA-sequencing (RNA-seq) was performed on the diagnostic marrows. We discovered a novel germline chromosomal structural variant in chromosome 1q32.2 within the TRAF3IP3 gene. TRAF3IP3 regulates B cell lymphopoiesis and this mutation likely resulted in a predisposition to leukemia by causing expansion of immature B-cell precursors which are highly vulnerable to secondary somatic mutations. This mutation has not been previously described in ALL, however based on the function of TRAF3IP3 in B cell lymphopoiesis, we conclude this likely represents a mutation predisposing to the development of leukemia. WES revealed this dyad had no shared SNVs that are associated with leukemia in the literature and that they had only a few shared SNVs within the leukemia samples, none of which were identified as clinically significant; which suggests the spectrum of their somatic mutations were distinctly different. Given the lack of concordance in their somatic mutational spectrum, we wondered if the two leukemia samples would exhibit a shared transcriptome, implying convergent leukemogenic pathways were altered within the two specimens since they were both clinically reported as hyperdiploid. In comparing the leukemia gene expression profiles identified by RNA-seq to 216 cases of sporadic B-ALL from the TARGET database (The Therapeutically Applicable Research to Generate Effective Treatments program), we discovered that these two leukemia samples did not cluster together but did cluster with other cases of childhood B-ALL. We suspect that this germline TRAF3IP3 mutation increased this dyad's susceptibility to leukemia development but that the somatic mutational spectrum drove the leukemia development and dictated its phenotype. This research may have identified a novel gene involved in leukemogenesis which may also be involved in de novo cases of ALL. Additional studies are needed to further characterize this TRAF3IP3 structural variant, the co-occurring somatic mutations within these leukemia samples and their combined role in leukemogenesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals LncRNA-mRNA Co-Expression Analysis Identifies AL133346.1/CCN2 as Biomarkers in Pediatric B-Cell Acute Lymphoblastic Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3803
Author(s):  
Marta Cuadros ◽  
Daniel J. García ◽  
Alvaro Andrades ◽  
Alberto M. Arenas ◽  
Isabel F. Coira ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Expression Profiles ◽  
Survival Curve ◽  
Lymphoblastic Leukemia ◽  
Cancer Cell Line ◽  
Differential Expression Pattern ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Low Levels

Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive neoplasia in which new targeted therapies are required. Long non-coding RNAs have recently emerged as promising disease-specific biomarkers for the clinic. Here, we identified pediatric B-ALL-specific lncRNAs and associated mRNAs by comparing the transcriptomic signatures of tumoral and non-tumoral samples. We identified 48 lncRNAs that were differentially expressed between pediatric B-ALL and healthy bone marrow samples. The most relevant lncRNA/mRNA pair was AL133346.1/CCN2 (previously known as RP11-69I8.3/CTGF), whose expression was positively correlated and increased in B-ALL samples. Their differential expression pattern and their strong correlation were validated in external B-ALL datasets (Therapeutically Applicable Research to Generate Effective Treatments, Cancer Cell Line Encyclopedia). Survival curve analysis demonstrated that patients with “high” expression levels of CCN2 had higher overall survival than those with “low” levels (p = 0.042), and this gene might be an independent prognostic biomarker in pediatric B-ALL. These findings provide one of the first detailed descriptions of lncRNA expression profiles in pediatric B-ALL and indicate that these potential biomarkers could help in the classification of leukemia subtypes and that CCN2 expression could predict the survival outcome of pediatric B-cell acute lymphoblastic leukemia patients.

scholarly journals Non-Coding RNA Signatures of B-Cell Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Princess D. Rodriguez ◽  
Hana Paculova ◽  
Sophie Kogut ◽  
Jessica Heath ◽  
Hilde Schjerven ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Transcriptome Profiling ◽  
Rna Seq ◽  
Protein Coding ◽  
Non Coding Rna ◽  
Technological Developments ◽  
Cell Acute Lymphoblastic Leukemia

Non-coding RNAs (ncRNAs) comprise a diverse class of non-protein coding transcripts that regulate critical cellular processes associated with cancer. Advances in RNA-sequencing (RNA-Seq) have led to the characterization of non-coding RNA expression across different types of human cancers. Through comprehensive RNA-Seq profiling, a growing number of studies demonstrate that ncRNAs, including long non-coding RNA (lncRNAs) and microRNAs (miRNA), play central roles in progenitor B-cell Acute Lymphoblastic Leukemia (B-ALL) pathogenesis. Furthermore, due to their central roles in cellular homeostasis and their potential as biomarkers, the study of ncRNAs continues to provide new insight into the molecular mechanisms of B-ALL. This article reviews the ncRNA signatures reported for all B-ALL subtypes, focusing on technological developments in transcriptome profiling and recently discovered examples of ncRNAs with biologic and therapeutic relevance in B-ALL.

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