scholarly journals Mutational profiling in acute lymphoblastic leukemia by RNA sequencing and chromosomal genomic array testing

2021 ◽  
Author(s):  
Cecilia Yeung ◽  
Xiaoyu Qu ◽  
Olga Sala‐Torra ◽  
David Woolston ◽  
Jerry Radich ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Rna Sequencing ◽  
Lymphoblastic Leukemia ◽  
Mutational Profiling ◽  
Genomic Array ◽  
Array Testing

scholarly journals Diagnostic evaluation of RNA sequencing for the detection of genetic abnormalities associated with Ph-like acute lymphoblastic leukemia (ALL)

2016 ◽  
Vol 58 (4) ◽  
pp. 950-958 ◽  
Author(s):  
Kai Lee Yap ◽  
Larissa V. Furtado ◽  
Kazuma Kiyotani ◽  
Emily Curran ◽  
Wendy Stock ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Rna Sequencing ◽  
Lymphoblastic Leukemia ◽  
Diagnostic Evaluation ◽  
Genetic Abnormalities

scholarly journals RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

Haematologica ◽  
2016 ◽  
Vol 101 (8) ◽  
pp. 941-950 ◽  
Author(s):  
V. Gianfelici ◽  
S. Chiaretti ◽  
S. Demeyer ◽  
F. Di Giacomo ◽  
M. Messina ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Rna Sequencing ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Implications ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Single-cell transcriptomics predicts relapse in MLL-rearranged acute lymphoblastic leukemia in infants

2020 ◽  
Author(s):  
Tito Candelli ◽  
Pauline Schneider ◽  
Patricia Garrido Castro ◽  
Luke A. Jones ◽  
Rob Pieters ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Risk Stratification ◽  
Single Cell ◽  
Rna Sequencing ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
List Type ◽  
Relapse Risk ◽  
Single Cell Rna Sequencing

AbstractInfants with MLL-rearranged acute lymphoblastic leukemia (ALL) undergo intense therapy to counter a highly aggressive leukemia with survival rates of only 30-40%. The majority of patients initially show therapy response, but in two-thirds of cases the leukemia returns, typically during treatment. Accurate relapse prediction would enable treatment strategies that take relapse risk into account, with potential benefits for all patients. Through analysis of diagnostic bone marrow biopsies, we show that single-cell RNA sequencing can predict future relapse occurrence. By analysing gene modules derived from an independent study of the gene expression response to the key drug prednisone, individual leukemic cells are predicted to be either resistant or sensitive to treatment. Quantification of the proportion of cells classified by single-cell transcriptomics as resistant or sensitive, accurately predicts the occurrence of future relapse in individual patients. Strikingly, the single-cell based classification is even consistent with the order of relapse timing. These results lay the foundation for risk-based treatment of MLL-rearranged infant ALL, through single-cell classification. This work also sheds light on the subpopulation of cells from which leukemic relapse arises. Leukemic cells associated with high relapse risk are characterized by a smaller size and a quiescent gene expression program. These cells have significantly fewer transcripts, thereby also demonstrating why single-cell analyses may outperform bulk mRNA studies for risk stratification. This study indicates that single-cell RNA sequencing will be a valuable tool for risk stratification of MLL-rearranged infant ALL, and shows how clinically relevant information can be derived from single-cell genomics.Key PointsSingle-cell RNA sequencing accurately predicts relapse in MLL-rearranged infant ALLIdentification of cells from which MLL-rearranged infant ALL relapses occur

scholarly journals NUTM1 Is a Rare but Recurrent Fusion Gene Partner in B Cell Precursor Acute Lymphoblastic Leukemia Associated with Increased Expression of Genes on Cytoband 10p12.31

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2823-2823
Author(s):  
Femke M. Hormann ◽  
Alex Q. Hoogkamer ◽  
H. Berna Beverloo ◽  
Aurélie Boeree ◽  
Ronald W. Stam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Rna Sequencing ◽  
Histone Acetyltransferase ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Population Based ◽  
Fusion Genes ◽  
Cell Precursor ◽  
Cytogenetic Aberration

Abstract INTRODUCTION In 20-25% of the pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) patients, the driving cytogenetic aberration is unknown. It is important to identify more primary lesions in this remaining B-other group to provide better risk stratification and identify possible treatment options. In this study, we aimed to identify novel recurrent fusion genes in BCP-ALL through RNA sequencing. METHODS We used paired-end total RNA Illumina sequencing to detect fusion genes with STAR-fusion and FusionCatcher in a population-based ALL cohort (n=71). We used Affymetrix U133 Plus2 expression arrays in a larger population-based ALL cohort (n=661) and an infant ALL cohort (n=70) to compare gene expression levels. Fluorescent in situ hybridization (FISH) was performed using Cytocell NUTM1 break-apart probe set MPH4800. RESULTS We identified an in-frame SLC12A6-NUTM1 fusion transcript composed of exons 1-2 of SLC12A6 fused to exons 3 to 8 of NUTM1 by RNA sequencing. Both genes are located on 15q14 within 5.3 Kb distance on opposite strands, and the fusion could result from an inversion. The fusion transcript is predicted to encode almost the total NUTM1 protein including the acidic binding domain for the histone acetyltransferase EP300. The SLC12A6-NUTM1 fusion case showed high NUTM1 expression, while NUTM1 expression was absent in the remaining cases. Using gene expression profiling, we identified four additional pediatric and two non-KMT2A-rearranged infant BCP-ALL cases with high NUTM1 expression. In the population-based cohort reflecting all different cytogenetic subtypes, these cases were restricted to the B-other group without known sentinel cytogenetic abnormalities. FISH showed a NUTM1 break apart pattern in all four tested NUTM1-positive cases indicative of a balanced translocation. RNA sequencing confirmed an ACIN1-NUTM1 fusion in one of the infant cases. We conclude that NUTM1 is normally not expressed in leukemic lymphoblasts, and that its expression can be induced by a gene fusion. The karyotypes of the predicted NUTM1 fusion cases combined with RNA sequencing data suggest that different chromosomal rearrangements are involved, likely resulting in different NUTM1 fusion partners. In literature, BRD9-NUTM1, IKZF1-NUTM1, and CUX1-NUTM1 fusions were reported in pediatric B-other cases, and BRD9-NUTM1 and ACIN1-NUTM1 fusions were reported in non-KMT2A-rearranged infants. Our combined aberrant gene expression and FISH results indicate that NUTM1 fusions occur in 2.4% (5/210) of pediatric and in 28% (2/7) of infant BCP-ALL cases without a sentinel cytogenetic aberration. The recurrence of NUTM1 aberrations in BCP-ALL cases without a known driver and the resulting expression of NUTM1 suggests that this fusion could be a new oncogenic driver in leukemia. All seven patients with a NUTM1 fusion achieved continuous complete remission with a median follow-up time of 8.3 years (range 4.8-13.8 years), suggesting that NUTM1 fusions in BCP-ALL have a favorable prognosis. To get an insight in the underlying biology, we compared gene expression between NUTM1-positive and NUTM1-negative pediatric B-other cases. We identified 130 differentially expressed probe sets (FDR ≤0.01) with a peculiar enrichment of those located on chromosome band 10p12.31 (Bonferroni adjusted p=4.05E-04). The genes in cytoband 10p12.31, including BMI1, were variably upregulated in 6/7 NUTM1-positive cases and positively correlated to NUTM1 expression levels. The NUTM1 protein is capable of binding and hereby stimulating the histone acetyltransferase activity of the EP300 protein. The EP300 protein preferentially binds a risk allele of BMI1 associated with increased risk for BCP-ALL. The BMI1 protein has been shown to convert BCR-ABL1-positive progenitor cells into BCR-ABL1-positive BCP-ALL cells. Hence, we postulate that NUTM1 fusion proteins contribute to leukemogenesis by stimulating EP300, leading to upregulation of BMI1 and other 10p12.31 genes in BCP-ALL. CONCLUSION NUTM1 fusions are a rare but recurrent event in BCP-ALL that seems to have a good prognosis. The NUTM1 fusions result in expression of the normally silent NUTM1 gene and are associated with upregulation of a cluster of genes on 10p12.31 including the leukemogenic BMI1 gene. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mutational profiling of acute lymphoblastic leukemia with testicular relapse

2017 ◽  
Vol 10 (1) ◽  
Author(s):  
Ling-Wen Ding ◽  
Qiao-Yang Sun ◽  
Anand Mayakonda ◽  
Kar-Tong Tan ◽  
Wenwen Chien ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Mutational Profiling

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 PS922 BENEFITS OF RNA SEQUENCING IN DETECTING RECURRENT AND NOVEL FUSION TRANSCRIPTS IN PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 415
Author(s):  
R. Shahswar ◽  
C. Haferlach ◽  
W. Walter ◽  
S.O. Twardziok ◽  
S. Hutter ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Rna Sequencing ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcripts

scholarly journals A comprehensive inventory of TLX1 controlled long non-coding RNAs in T-cell acute lymphoblastic leukemia through polyA+ and total RNA sequencing

Haematologica ◽  
2018 ◽  
Vol 103 (12) ◽  
pp. e585-e589 ◽  
Author(s):  
Karen Verboom ◽  
Wouter Van Loocke ◽  
Pieter-Jan Volders ◽  
Bieke Decaesteker ◽  
Francisco Avila Cobos ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Rna Sequencing ◽  
Lymphoblastic Leukemia ◽  
Total Rna ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Non Coding Rnas

scholarly journals Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases

2018 ◽  
Vol 115 (50) ◽  
pp. E11711-E11720 ◽  
Author(s):  
Jian-Feng Li ◽  
Yu-Ting Dai ◽  
Henrik Lilljebjörn ◽  
Shu-Hong Shen ◽  
Bo-Wen Cui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Rna Sequencing ◽  
Large Scale ◽  
Lymphoblastic Leukemia ◽  
International Study ◽  
Disease Classification ◽  
Cell Precursor

Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3–PBX1 fusions, ETV6–RUNX1–positive/ETV6–RUNX1–like, DUX4 fusions, ZNF384 fusions, BCR–ABL1/Ph–like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH–CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4–HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.

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