12 research outputs found

    The Expression Pattern of the Pre-B Cell Receptor Components Correlates with Cellular Stage and Clinical Outcome in Acute Lymphoblastic Leukemia

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    <div><p>Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. However, the cellular stage at which BCP-ALL are arrested and whether this relates to expression of the pre-BCR components (<i>IGHM</i>, <i>IGLL1</i> and <i>VPREB1)</i> is still unclear. Here, we show differential protein expression and copy number variation (CNV) patterns of the pre-BCR components in pediatric BCP-ALL. Moreover, analyzing six BCP-ALL data sets (n = 733), we demonstrate that <i>TCF3-PBX1</i> ALL express high levels of <i>IGHM</i>, <i>IGLL1</i> and <i>VPREB1</i>, and are arrested at the pre-B stage. By contrast, <i>ETV6-RUNX1</i> ALL express low levels of <i>IGHM</i> or <i>VPREB1</i>, and are arrested at the pro-B stage. Irrespective of subtype, ALL with high levels of <i>IGHM</i>, <i>IGLL1</i> and <i>VPREB1</i> are arrested at the pre-B stage and correlate with good prognosis in high-risk pediatric BCP-ALL (n = 207). Our findings suggest that BCP-ALL are arrested at different cellular stages, which relates to the expression pattern of the pre-BCR components that could serve as prognostic markers for high-risk pediatric BCP-ALL patients.</p></div

    GSEA reveals molecular signature similarities between the <i>IGHM</i><sup>+</sup><i>IGLL1</i><sup>+</sup><i>VPREB1</i><sup>+</sup> BCP-ALL and normal pre-B cells.

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    <p>(A) The BCP-ALL in data set GSE11877, including 207 high-risk patient samples, were classified into four clusters according the expression levels of <i>IGHM</i>, <i>IGLL1</i> and <i>VPREB1</i>: <i>IGHM+IGLL1+VPREB1+</i> (Cluster 1), <i>IGHM+IGLL1+/-VPREB1+/-</i> (not including <i>IGHM+IGLL1+VPREB1+</i>) (Cluster 2), <i>IGHM-IGLL1+/-VPREB1+/-</i> (not including <i>IGHM-IGLL1-VPREB1-</i>) (Cluster 3) and <i>IGHM-IGLL1-VPREB1-</i> (Cluster 4). (B) Genes highly expressed in pre-B cells are enriched in Cluster 1. Left: The pre-B signature was identified using supervised comparison in data set GSE45460. Middle: Heat map of the pre-B signature in Cluster 1 and the remaining ALL. Right: Enrichment plot shows the enrichment of pre-B signature in the Cluster 1. (C) Genes highly expressed in Cluster 1 are enriched in pre-B cells. Left: The top 400 genes highly expressed in Cluster 1 (Cluster 1 signature) were identified using supervised comparison. Middle: Heat map of the Cluster 1 signature in healthy pre-B cells. Right: Enrichment plot shows the enrichment of Cluster 1 signature in healthy pre-B cells. (D) Pie-chart shows the distribution of genetic subtypes in clusters 1–4. (E) Genes highly expressed in pre-B cells are enriched in the <i>TCF3-PBX1</i> ALL from Cluster 1 but not that from other clusters. Left: Heat map of the pre-B signature in the <i>TCF3-PBX1</i> ALL from Cluster1. Right: Enrichment plot shows the enrichment of pre-B signature in the <i>TCF3-PBX1</i> ALL from Cluster 1. (F) Genes highly expressed in pre-B cells are enriched in Cluster 1 without <i>TCF3-PBX1</i>. Left: Heat map of the pre-B signature in the Cluster1 without <i>TCF3-PBX1</i>. Right: Enrichment plot shows the enrichment of pre-B signature in Cluster 1 without the <i>TCF3-PBX1</i> ALL.</p

    The expression pattern of pre-BCR components associates with the clinical outcomes in high-risk patient group.

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    <p>(A) The percentage of MRD 29 positive patients was compared among clusters 1–4 using Fisher's exact test. MRD 29: minimal residual disease at day 29. (B-E) The Kaplan-Meier Log rank Survival analysis was performed to compare event free survival (B and C) and overall survival (D and E) of the 207 high-risk patients. Survival probabilities between patients within different clusters (1–4) are shown.</p

    GSEA reveals molecular signature similarities between the <i>TCF3-PBX1</i> BCP-ALL and normal pre-B cells.

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    <p>(A) Genes highly expressed in pre-B cells are enriched in the <i>TCF3-PBX1</i>. Left: The top 400 genes highly expressed in healthy pre-B cells (pre-B signature) were identified using supervised comparison in data set GSE45460. Middle: Heat map of the pre-B signature in the <i>TCF3-PBX1</i> and the remaining ALL in data set GSE12995. Right: Enrichment plot shows the enrichment of pre-B signature in the <i>TCF3-PBX1</i>. The upper part of the Fig shows the enrichment score (NES), which is calculated by ranked ordered gene set and increasing the score when a gene is in the set and decreasing it when it is not. Each blue line represents a hit from the gene set. The more hits among the top up- or downregulated genes, the more likely a significant gene set enrichment score is gotten. The lower portion of the Fig shows the rank ordered genes for the <i>TCF3-PBX1</i> when compared to other ALL, with genes being highly expressed to the far left and downregulated genes to the right. (B) Genes highly expressed in the <i>TCF3-PBX1</i> are enriched in pre-B cells. Left: The top 400 genes highly expressed in <i>TCF3-PBX1</i> (<i>TCF3-PBX1</i> signature) were identified using supervised comparison. Middle: Heat map of the <i>TCF3-PBX1</i> signature in healthy pre-B cells. Right: Enrichment plot shows the enrichment of <i>TCF3-PBX1</i> signature in healthy pre-B cells.</p

    The pre-BCR components show distinct mRNA expression patterns in BCP-ALL and normal B cells.

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    <p>(A) Heat map shows the expression patterns of the pre-BCR components in childhood BCP-ALL (GSE12995). (B) The graphs show the expression patterns of <i>IGHM</i>, <i>VPREB1</i> and <i>IGLL1</i> in 733 BCP-ALL patient samples from six cohorts (GSE12995, Blood2003, GSE177031, GSE26281, GSE13425 and GSE47051). All patient samples were evenly divided into quartiles according to the expression level of <i>IGHM</i>, <i>VPREB1</i> or <i>IGLL1</i>. (C) Heat map shows the expression patterns of the pre-BCR components in a normal B-cell data set (GSE45460). HH, High Hyperdiploid; iB, immature B cells.</p

    GSEA reveals molecular signature similarities between the <i>ETV6-RUNX1</i> BCP-ALL and normal pro-B cells.

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    <p>(A) Genes highly expressed in pro-B cells are enriched in the <i>ETV6-RUNX1</i>. Left: The top 400 genes highly expressed in pro-B cells (pro-B signature) were identified using supervised comparison in data set GSE45460. Middle: Heat map of the pro-B signature in the <i>ETV6-RUNX1</i> and the remaining ALL in data set GSE12995. Right: Enrichment plot show the enrichment of pro-B signature in the <i>ETV6-RUNX1</i> (B) Genes highly expressed in the <i>ETV6-RUNX1</i> are enriched in pro-B cells. Left: The top 400 genes highly expressed in the <i>ETV6-RUNX1</i> (<i>ETV6-RUNX1</i> signature) were identified using supervised comparison. Middle: Heat map of the <i>ETV6-RUNX1</i> signature in healthy pro-B cells. Right: Enrichment plot showing the enrichment of the <i>ETV6-RUNX1</i> signature in healthy pro-B cells.</p

    The pre-BCR components show differential protein expression and copy number variation patterns in BCP-ALL patients.

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    <p>(A) Histograms show the differential expression patterns of IGHM, VPREB1 and IGLL1 in CD19<sup>+</sup>-blasts from two patients (#12 and #15). Bone marrow samples were stained with antibodies against μ heavy chain (IGHM), CD179a (VPREB1) and CD179b (IGLL1), and then analyzed by flow cytometry. (B) Copy number variation (CNV) analysis shows the genetic aberration frequencies of the pre-BCR in 123 patients. The pre-BCR is defined as aberrant when one or more of the pre-BCR components showed CNVs. (C) CNV analyses show the percentage of amplifications and/or deletions of <i>IGHM</i>, <i>VPREB1</i> and <i>IGLL1</i>. HH, High Hyperdiploid.</p

    Decreased intracellular CD23 level and normal CD23 and ADAM10 mRNA transcripts.

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    <p>The CD23 total (Total) protein pool in LxT1 B cells was lower than that of the control (A, left), with a similar reduction in CD23 cell surface only (Sur) (A, right) and intracellular (intra) levels (B). Representative of one experiment, n = 3/genotype. (C) Comparable CD23 mRNA levels in B cells from LxT1 and B6 mice. (D) Similar levels of ADAM10 mRNA expression in PLN B cells from LxT1 and B6 mice. RNA isolated from CD19<sup>+</sup> splenic (SPL) and peripheral lymph node (PLN) B cells was analyzed by q-PCR. CD23 and ADAM10 transcripts were normalized to 18S rRNA. Representative of one experiment, n = 3/genotype.</p

    LxT1 mice display normal natural IgE levels.

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    <p>Similar serum IgE levels in LxT1 and B6 mice in the absence of active immunization. Each symbol represents an individual mouse. Black bar represents mean values. Representative of 2 experiments.</p

    Mutations in the CD23 coding region in different mouse strains.

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    <p>CD23 mutations (bold) are reported in the CGDSNP database and literature <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062851#pone.0062851-Ford2" target="_blank">[12]</a>. The mutations in CD23 coding region in LxT1 are demonstrated by sequencing.</p
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