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.

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 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/).

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 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 Prognostic significance of protein-coding and long non-coding RNA expression profile in T-cell acute lymphoblastic leukemia

2021 ◽  
Author(s):  
Deepak Verma ◽  
Shruti Kapoor ◽  
Disha Sharma ◽  
Jay Singh ◽  
Gunjan Sharma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profile ◽  
Lymphoblastic Leukemia ◽  
High Expression ◽  
Protein Coding ◽  
Non Coding Rna ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Long Non Coding Rna

T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy associated with poor outcome. To unravel gene-expression profile of immunophenotypic subtypes of T-ALL, we did transcriptome analysis in 35 cases. We also analyzed the prognostic relevance of 23 targets: protein-coding genes, histone modifiers and long non-coding RNA (lncRNA) expression profile, identified on RNA sequencing, on an independent cohort of 99 T-ALL cases. We found high expression of MEF2C to be associated with prednisolone resistance (p=0.048) and CD34 expression (p=0.012). BAALC expression was associated with expression of CD34 (p=0.032) and myeloid markers (p=0.021). XIST and KDM6a expression levels were higher in females (p=0.047 and 0.011, respectively). Post-induction minimal residual disease (MRD) positivity was associated with high lncRNA PCAT18 (p=0.04), HHEX (p=0.027) and MEF2C (p=0.007). Early thymic precursor (ETP-ALL) immunophenotype was associated with high expression of MEF2C (p=0.003), BAALC (p=0.003), LYL1 (p=0.01), LYN (p=0.01), XIST (p=0.02) and low levels of ST20 (p=0.007) and EML4 (p=0.03). On survival analysis, MEF2C high expression emerged as significant predictor of 3-year event free survival (EFS) (low 71.78+6.58% vs high 36.57+10.74%, HR 3.5, p=0.0003) and overall survival (OS) (low 94.77+2.96% vs high 78.75+8.45%, HR 4.88, p=0.016) in our patients. LncRNA MALAT1 low expression also emerged as predictor inferior OS (low 76.02+10.48 vs high 94.11+3.31, HR 0.22, p=0.027). Keywords: RNA-Sequencing, T-cell acute lymphoblastic Leukemia, Early thymic precursor, LncRNA, Gene expression profile.

scholarly journals Ultraconserved long non-coding RNA uc.112 is highly expressed in childhood T versus B-cell acute lymphoblastic leukemia

2020 ◽  
Author(s):  
Pablo Ferreira das Chagas ◽  
Graziella Ribeiro de Sousa ◽  
Márcio Hideki Kodama ◽  
Carlos Alberto Oliveira de Biagi Junior ◽  
José Andres Yunes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Non Coding Rna ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Long Non Coding Rna

scholarly journals Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 32
Author(s):  
Oscar Molina ◽  
Alex Bataller ◽  
Namitha Thampi ◽  
Jordi Ribera ◽  
Isabel Granada ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Chromosome Doubling ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Standard Of Care ◽  
Diagnostic Methods ◽  
Molecular Features ◽  
Cell Acute Lymphoblastic Leukemia

Hypodiploidy with less than 40 chromosomes is a rare genetic abnormality in B-cell acute lymphoblastic leukemia (B-ALL). This condition can be classified based on modal chromosome number as low-hypodiploidy (30–39 chromosomes) and near-haploidy (24–29 chromosomes), with unique cytogenetic and mutational landscapes. Hypodiploid B-ALL with <40 chromosomes has an extremely poor outcome, with 5-year overall survival rates below 50% and 20% in childhood and adult B-ALL, respectively. Accordingly, this genetic feature represents an adverse prognostic factor in B-ALL and is associated with early relapse and therapy refractoriness. Notably, half of all patients with hypodiploid B-ALL with < 40 chromosomes cases ultimately exhibit chromosome doubling of the hypodiploid clone, resulting in clones with 50–78 chromosomes. Doubled clones are often the major clones at diagnosis, leading to “masked hypodiploidy”, which is clinically challenging as patients can be erroneously classified as hyperdiploid B-ALL. Here, we summarize the main cytogenetic and molecular features of hypodiploid B-ALL subtypes, and provide a brief overview of the diagnostic methods, standard-of-care treatments and overall clinical outcome. Finally, we discuss molecular mechanisms that may underlie the origin and leukemogenic impact of hypodiploidy and may open new therapeutic avenues to improve survival rates in these patients.

scholarly journals MEK1 Inhibitor Selumetinib Sensitizes Precursor B-Cell Acute Lymphoblastic Leukemia Cells (B-ALL) to Dexamethasone through Modulation of mTOR Activity and Stimulation of Autophagy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4917-4917
Author(s):  
Anna Polak ◽  
Przemyslaw Kiliszek ◽  
Tomasz Sewastianik ◽  
Maciej Szydlowski ◽  
Ewa Jablonska ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Lymphoblastic Leukemia ◽  
Apoptotic Cell Death ◽  
Leukemia Cells ◽  
Erk Pathway ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Glucocorticoids (GC) have been used for decades in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) in children and adults. Induction of apoptosis is thought to be the principal effector mechanism of GC's action, but recent studies highlight the role of autophagy upstream of apoptotic cell death (Laane et al 2009). Resistance to GCs is a major adverse prognostic factor, however the molecular mechanisms leading to GC resistance are not completely understood. Herein, we sought to elucidate the molecular mechanisms driving GC-resistance in precursor B-cell acute lymphoblastic leukemia cells and in vitro characterize the therapeutic potential of targeted intervention in these mechanisms. To identify molecular mechanisms involved in GC resistance, we performed gene set enrichment analysis of gene expression profiles GC-sensitive and -resistant B-ALL blasts using publicly available datasets and GenePattern program. Resistant cells exhibited significantly higher expression of MAPK/ERK pathway components (p<.002, FDR=0.13). To validate these findings, we assessed DEX sensitivity in ALL cells with high (SEMK2) or undetectable (RS4;11) activity of MAPK/ERK pathway. SEMK2 cells were resistant to DEX, whereas RS4;11 were highly sensitive to this drug. In GC-resistant cell line SEMK2, inhibition of MEK1 kinase with SEL completely abrogated ERK and p90RSK phosphorylation and increased sensitivity to GC by 1.8-2.6-fold. Similar pattern was observed in primary ALL blasts from 19 of 23 tested patients. Overexpression of a constitutively active MEK mutant in GC-sensitive cells (RS4;11) reversed sensitivity of these cells to DEX. Since GC in leukemic cells induce autophagic cell death, we assessed LC3 processing, MDC staining (a dye of autophagolysosomes) and GFP-LC3 relocalization in cells incubated with either DEX, SEL or combination of drugs. Either drug alone caused only marginal change in the level of these markers, but their combination markedly increased autophagic flux. Since mTORC1 is the critical regulator of autophagy, we assessed the activity of mTORC1 following DEX/SEL co-treatment and found that the combination resulted in a marked decrease of p4E-BP1, an mTORC1 substrate. Finally, to assess whether induction of autophagy is required for the observed synergy between SEL and DEX we used an shRNA approach to silence beclin-1 (BCN1), a gene required for autophagosome formation, and assessed cellular responses to DEX/SEL co-treatment. In control cells transduced with non-targeting shRNA, SEL sensitized cells to DEX, but in BCN1-deficient cells, the synergy of DEX and SEL was markedly decreased. Taken together, we show that MEK1 inhibitor selumetinib enhances DEX toxicity in GC-resistant B-ALL cells. The underlying mechanism of this interaction involves inhibition of mTORC1 signaling pathway and induction of autophagy that leads to apoptotic cell death. Disclosures No relevant conflicts of interest to declare.

Role of Spleen Tyrosine Kinase Signaling in Early B Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3092-3092
Author(s):  
Tatiana Perova ◽  
Lauryl Nutter ◽  
Irina Matei ◽  
Ildiko Grandal ◽  
Polly Pine ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Employment Equity ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Equity Ownership ◽  
All Treatment

Abstract Abstract 3092 Poster Board III-29 Introduction Early B cell acute lymphoblastic leukemia (B-ALL) is the most common type of childhood malignancy, characterized by abnormal accumulation and proliferation of progenitor-B or precursor-B (pre-B) cells. Current challenges associated with B-ALL treatment include fatal relapses, treatment-related toxicities and long-term morbidities underscoring a need to develop new targeted therapies aimed at eradicating leukemia cells and their stem cells. To achieve this, a better understanding of molecular mechanisms involved in leukemia initiation and progression is required. Our laboratory developed p53-/- PrkdcSCID/SCID double mutant (DM) strain as a mouse model of early B-ALL. We showed that DM leukemias progress through discrete developmental stages of leukemogenesis despite the absence of a pre-B cell receptor (pre-BCR), a crucial checkpoint in B cell development. Spleen tyrosine kinase (SYK), a key proximal component of pre-BCR signaling, was activated in the DM leukemias despite the absence of pre-BCR and was required for their survival. Approximately 70% of pediatric pre-B-ALLs also do not express pre-BCR, which lead us to investigate SYK signaling in human pre-B-ALL and to test potential therapeutic application of SYK inhibition in these leukemias. Patients and Methods We examined 22 viably frozen primary pediatric pre-B-ALL bone marrow samples to test their responses to SYK inhibition in vitro and in vivo and have investigated the molecular basis for aberrant SYK-mediated signaling in B-ALL. Results Western blot analyses revealed that SYK and BLNK, a dominant target of SYK, were expressed in pre-B-ALL patient samples. The majority of human pre-B ALL samples tested (14/22) displayed significantly attenuated proliferation in the presence of SYK inhibitors suggesting that SYK is necessary for their survival and/or proliferation. Treatment with SYK inhibitor R406 prevented phosphorylation of downstream SYK targets including BLNK and PLC-γ2. We are continuing to study the effects of SYK inhibition using phospho-flow cytometry and genome wide expression arrays. Preliminary data will also be presented on therapeutic efficacy of an orally bioavailable form of R406-mediated SYK inhibition in vivo by xenotransplantation of human leukemias into immuno-deficient mice. Conclusions Understanding the molecular mechanisms of pre-BCR-independent SYK activation involved in proliferation and survival of leukemic blasts may provide a rational basis for development of effective treatment for ALL. Specifically, targeted therapeutic inhibition of SYK signaling may be effective B-ALL treatment that may improve outcomes of current treatment regiments with minimal additional treatment-related toxicity. Disclosures Pine: Rigel Pharmaceuticals: Employment, Equity Ownership. Hitoshi:Rigel Pharmaceuticals: Employment, Equity Ownership.

Sign in / Sign up

Export Citation Format

Share Document