Differential Gene Expression Patterns and Interaction Networks in BCR-ABL–Positive and –Negative Adult Acute Lymphoblastic Leukemias

Purpose To identify gene expression patterns and interaction networks related to BCR-ABL status and clinical outcome in adults with acute lymphoblastic leukemia (ALL). Patients and Methods DNA microarrays were used to profile a set of 54 adult ALL specimens from the Medical Research Council UKALL XII/Eastern Cooperative Oncology Group E2993 trial (21 p185BCR-ABL–positive, 16 p210BCR-ABL–positive and 17 BCR-ABL–negative specimens). Results Using supervised and unsupervised analysis tools, we detected significant transcriptomic changes in BCR-ABL–positive versus –negative specimens, and assessed their validity in an independent cohort of 128 adult ALL specimens. This set of 271 differentially expressed genes (including GAB1, CIITA, XBP1, CD83, SERPINB9, PTP4A3, NOV, LOX, CTNND1, BAALC, and RAB21) is enriched for genes involved in cell death, cellular growth and proliferation, and hematologic system development and function. Network analysis demonstrated complex interaction patterns of these genes, and identified FYN and IL15 as the hubs of the top-scoring network. Within the BCR-ABL–positive subgroups, we identified genes overexpressed (PILRB, STS-1, SPRY1) or underexpressed (TSPAN16, ADAMTSL4) in p185BCR-ABL–positive ALL relative to p210BCR-ABL–positive ALL. Finally, we constructed a gene expression- and interaction-based outcome predictor consisting of 27 genes (including GRB2, GAB1, GLI1, IRS1, RUNX2, and SPP1), which correlated with overall survival in BCR-ABL–positive adult ALL (P = .0001), independent of age (P = .25) and WBC count at presentation (P = .003). Conclusion We identified prominent molecular features of BCR-ABL–positive adult ALL, which may be useful for developing novel therapeutic targets and prognostic markers in this disease.

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Differential Gene Expression Patterns and Interaction Networks in BCR/ABL Positive and Negative Adult Acute Lymphoblastic Leukemias.

Blood ◽

10.1182/blood.v108.11.1836.1836 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1836-1836

Author(s):

Dejan Juric ◽

Norman J. Lacayo ◽

Meghan C. Ramsey ◽

Janis Racevskis ◽

Peter H. Wiernik ◽

...

Keyword(s):

Gene Expression ◽

Differential Gene Expression ◽

Expression Profiles ◽

Lymphoblastic Leukemia ◽

Expression Patterns ◽

Cellular Growth ◽

Interaction Networks ◽

Pcr Analysis ◽

Interaction Patterns ◽

Differential Gene

Abstract BCR/ABL is associated with an unfavorable prognosis in adults with acute lymphoblastic leukemia (ALL). We used DNA microarrays to identify gene expression profiles and molecular interaction networks related to BCR/ABL status and clinical outcome in a set of 54 adult ALL specimens from the MRC UKALL XII/ECOG E2993 intergroup study (21 p185BCR/ABL- and 16 p210BCR/ABL-positive and 17 BCR/ABL negative). In order to avoid biases associated with commonly used sample amplification procedures, we have implemented an indirect two-step labeling protocol based on signal amplification by use of dendrimer technology. Using a two-class, non-parametric t-test and a false discovery rate cutoff of 5%, we identified 271 genes (including GAB1, CIITA, XBP1, CD83, SERPINB9, PTP4A3, NOV, LOX, CTNND1, BAALC and RAB21) as differentially expressed in BCR/ABL positive ALL compared with BCR/ABL negative ALL. They separate these two classes of adult ALL with an overall accuracy of 93% and are enriched for three highly relevant biological functions: Cellular Growth and Proliferation (57 genes, p = 0.004–0.044), Cell Death (49 genes, p = 0.0007–0.049), and Hematological System Development and Function (40 genes, p = 0.00004–0.049). Network analysis demonstrated complex interaction patterns of these genes, and identified FYN and IL15 as the hubs of the top-scoring network. We confirmed these findings by both qRT-PCR analysis of the initial set of samples and by cross-platform validation in an independent cohort of 128 adult ALL specimens. In addition, within the BCR/ABL positive subgroup, we identified 14 clones found to be over-expressed (TSPAN16, ADAMTSL4) or under-expressed (PILRB, STS-1, SPRY1) in p185BCR-ABL- relative to p210BCR-ABL-ALL. In a nearest-centroid classification, these clones correctly predict the BCR/ABL subtype with a cross-validated prediction accuracy of 95%. No differential gene expression was detected among Rho family GTPases and their known interaction partners. Finally, we constructed a gene expression- and interaction-based outcome predictor consisting of 27 genes (including GRB2, GAB1, GLI1, IRS1, RUNX2 and SPP1), which strongly correlated with overall survival in BCR/ABL positive adult ALL (p=0.0001), independently of other clinical parameters such as age (p=0.25) and white blood cell count at presentation (p = 0.003). These findings may be useful for developing novel therapeutic targets and prognostic markers in adult ALL.

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Gene expression patterns in bone following lipopolysaccharide stimulation

Cellular & Molecular Biology Letters ◽

10.2478/s11658-014-0216-2 ◽

2014 ◽

Vol 19 (4) ◽

Cited By ~ 4

Author(s):

Jing Yang ◽

Nan Su ◽

Xiaolan Du ◽

Lin Chen

Keyword(s):

Gene Expression ◽

Bone Formation ◽

Real Time ◽

Real Time Pcr ◽

Early Stage ◽

System Development ◽

Expression Patterns ◽

Osteoclast Differentiation ◽

Gene Expression Patterns ◽

Expression Levels

AbstractBone displays suppressed osteogenesis in inflammatory diseases such as sepsis and rheumatoid arthritis. However, the underlying mechanisms have not yet been clearly explained. To identify the gene expression patterns in the bone, we performed Affymetrix Mouse Genome 430 2.0 Array with RNA isolated from mouse femurs 4 h after lipopolysaccharide (LPS) administration. The gene expressions were confirmed with real-time PCR. The serum concentration of the N-terminal propeptide of type I collagen (PINP), a bone-formation marker, was determined using ELISA. A total of 1003 transcripts were upregulated and 159 transcripts were downregulated (more than twofold upregulation or downregulation). Increased expression levels of the inflammation-related genes interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) were confirmed from in the period 4 h to 72 h after LPS administration using real-time PCR. Gene ontogene analysis found four bone-related categories involved in four biological processes: system development, osteoclast differentiation, ossification and bone development. These processes involved 25 upregulated genes. In the KEGG database, we further analyzed the transforming growth factor β (TGF-β) pathway, which is strongly related to osteogenesis. The upregulated bone morphogenetic protein 2 (BMP2) and downregulated inhibitor of DNA binding 4 (Id4) expressions were further confirmed by real-time PCR after LPS stimulation. The osteoblast function was determined through examination of the expression levels of core binding factor 1 (Cbfa1) and osteocalcin (OC) in bone tissues and serum PINP from 4 h to 72 h after LPS administration. The expressions of OC and Cbfa1 decreased 6 h after administration (p < 0.05). Significantly suppressed PINP levels were observed in the later stage (from 8 h to 72 h, p < 0.05) but not in the early stage (4 h or 6 h, p > 0.05) of LPS stimulation. The results of this study suggest that LPS induces elevated expressions of skeletal system development- and osteoclast differentiation-related genes and inflammation genes at an early stage in the bone. The perturbed functions of these two groups of genes may lead to a faint change in osteogenesis at an early stage of LPS stimulation. Suppressed bone formation was found at later stages in response to LPS stimulation.

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Evolution of Gene Expression Signatures in Relapsed Childhood Acute Lymphoblastic Leukemia Differs Based on Timing of Relapse.

Blood ◽

10.1182/blood.v112.11.3345.3345 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3345-3345

Author(s):

Deepa Bhojwani ◽

Jinhua Wang ◽

Jun J Yang ◽

Debra Morrison ◽

Meenakshi Devidas ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Expression Patterns ◽

Childhood Acute Lymphoblastic Leukemia ◽

Late Relapse ◽

Gene Expression Patterns ◽

Early Relapse ◽

Over Expression

Abstract The outcome for childhood acute lymphoblastic leukemia (ALL) following marrow relapse remains bleak in spite of numerous approaches to further intensify therapy. Understanding the biological basis of relapse and chemoresistance, as well as identifying and validating potential new targets, are the goals of our study. Previously we determined global gene expression patterns of matched diagnosis and relapse leukemic blasts in 32 patients (64 samples) with childhood B-precursor ALL using Affymetrix U133A arrays (Blood2006;108(2):711–7). We now have extended this analysis to 60 patients (120 samples). Thirty-six patients relapsed early (within 36 months of initial diagnosis), while 24 patients relapsed late. Within the TEL/AML1 subset (n=12 patients), time to relapse was inversely proportional to the correlation co-efficient of expression profiles of the diagnosis and relapse matched pair samples, suggesting that the later the relapse, the more distinct the relapse clone is from the diagnostic clone. A supervised pairwise analysis in all 60 patients identified 292 probesets that were differentially expressed between diagnosis and relapse (FDR < 10%). In a relative enrichment analysis, multiple genes mediating cell death were down-regulated at relapse (p=0.00003), suggesting that the leukemia cells had evolved mechanisms to enhance survival. These included p21, TNFPAI3, RIPK2, BCLAF1, STK17B. In concert, DNA replication genes were up-regulated at relapse (p=0.00002). Differences in pathways leading to early vs. late relapse were evident. Early relapse was characterized by an over-expression of cell cycle genes reflecting a proliferative state. At the time of relapse, a marked over-representation of genes involved in the progression through the M phase of the cell cycle was observed in early relapse compared to late relapse (p=1.3E-08). Late relapse was characterized by the over-expression of genes involved in nucleoside biosynthesis, particularly targets of antifolates (DHFR, MTHFD1, TYMS). A small number of gene expression patterns were common to both early and late relapse, including up-regulation at relapse of BIRC5 (survivin): an attractive target for therapeutic intervention. In conclusion, analysis of an expanded cohort of matched diagnosis/relapse pairs has validated and extended our previous findings that early relapse is associated with a proliferative gene expression signature. In addition we have now identified pathways operative in late relapse. Targeting these individual genes and pathways may lead to innovative strategies to treat or prevent relapsed ALL.

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Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

New England Journal of Medicine ◽

10.1056/nejmoa033513 ◽

2004 ◽

Vol 351 (6) ◽

pp. 533-542 ◽

Cited By ~ 417

Author(s):

Amy Holleman ◽

Meyling H. Cheok ◽

Monique L. den Boer ◽

Wenjian Yang ◽

Anjo J.P. Veerman ◽

...

Keyword(s):

Gene Expression ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Expression Patterns ◽

Response To Treatment ◽

Leukemia Cells ◽

Gene Expression Patterns ◽

Drug Resistant

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Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Frontiers of Medicine ◽

10.1007/s11684-020-0821-6 ◽

2021 ◽

Author(s):

Jianfeng Li ◽

Yuting Dai ◽

Liang Wu ◽

Ming Zhang ◽

Wen Ouyang ◽

...

Keyword(s):

Gene Expression ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Molecular Subtypes ◽

Lymphoblastic Leukemia ◽

Expression Patterns ◽

Therapeutic Targets ◽

Genetic Alterations ◽

Gene Expression Patterns ◽

Cell Precursor

AbstractB-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

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