Kinase domain mutants of Bcr enhance Bcr-Abl oncogenic effects

Perazzona, Bastianella; Lin, Hui-Kuan; Wang, Y; Arlinghaus, Ralph B.

doi:10.1038/sj.onc.1210851

Cited by 5 publications

(3 citation statements)

References 18 publications

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“…These findings not only show that the down-regulation of p96 ABL/BCR and not that of BCR is responsible for the block of proliferation but also indicate that endogenous BCR does not play any role for the leukemogenic potential of either TEL/ABL or BCR/ABL. This confirms several studies showing that BCR has even a negative impact on BCR/ABL activation and its oncogenic potential [ 28 , 29 , 30 , 31 ]. In order to investigate whether apoptosis is important for the inhibition of proliferation, we stained the Ph + PD-LTCs cells with 7-AAD and measured the apoptosis rate by flow cytometry.…”

Section: Resultssupporting

confidence: 91%

The Functional Interplay Between the t(9;22)-Associated Fusion Proteins BCR/ABL and ABL/BCR in Philadelphia Chromosome-Positive Acute Lymphatic Leukemia

et al. 2015

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The hallmark of Philadelphia chromosome positive (Ph+) leukemia is the BCR/ABL kinase, which is successfully targeted by selective ATP competitors. However, inhibition of BCR/ABL alone is unable to eradicate Ph+ leukemia. The t(9;22) is a reciprocal translocation which encodes not only for the der22 (Philadelphia chromosome) related BCR/ABL, but also for der9 related ABL/BCR fusion proteins, which can be detected in 65% of patients with chronic myeloid leukemia (CML) and 100% of patients with Ph+ acute lymphatic leukemia (ALL). ABL/BCRs are oncogenes able to influence the lineage commitment of hematopoietic progenitors. Aim of this study was to further disclose the role of p96ABL/BCR for the pathogenesis of Ph+ ALL. The co-expression of p96ABL/BCR enhanced the kinase activity and as a consequence, the transformation potential of p185BCR/ABL. Targeting p96ABL/BCR by RNAi inhibited growth of Ph+ ALL cell lines and Ph+ ALL patient-derived long-term cultures (PD-LTCs). Our in vitro and in vivo stem cell studies further revealed a functional hierarchy of p96ABL/BCR and p185BCR/ABL in hematopoietic stem cells. Co-expression of p96ABL/BCR abolished the capacity of p185BCR/ABL to induce a CML-like disease and led to the induction of ALL. Taken together our here presented data reveal an important role of p96ABL/BCR for the pathogenesis of Ph+ ALL.

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Section: Resultssupporting

confidence: 91%

The Functional Interplay Between the t(9;22)-Associated Fusion Proteins BCR/ABL and ABL/BCR in Philadelphia Chromosome-Positive Acute Lymphatic Leukemia

et al. 2015

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“…The function of the normal BCR gene product is not clear, but the BCR/ABL fusion protein has been researched deeply. The abnormal expression of BCR/ABL may lead to many diseases, including chronic granulocytes leukemia, acute lymphocyte leukemia and the related pathways, including endometrial cancer and the PI3K/Akt pathway [48][49][50][51]. However, there is limited research on the methylation status of the BCR gene in liver cancer.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of aberrantly expressed methylation genes in human hepatocellular carcinoma

Zhen

Ning

et al. 2020

Bioscience Reports

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Objectives: To identify the prognostic value of aberrantly methylated differentially expressed genes (DEGs) in hepatocellular carcinoma (HCC) and to explore the underlying mechanisms of tumorigenesis. Methods: Gene expression profiles (GSE65372 and GSE37988) were analyzed using GEO2R to obtain aberrantly methylated DEGs. Functional enrichment analysis of screened genes was performed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Cytoscape software was used to analyze the PPI network and to select hub genes. Transcriptional and proteinic expression data of hub genes were obtained through UALCAN and the Human Protein Reference Database. Finally, we analyzed the prognostic value of hub genes with the Kaplan-Meier Plotter and MethSurv database. Results: In total, 24 up-hypomethylated oncogenes and 37 down-hypermethylated tumor suppressor genes (TSGs) were identified, and 8 hub genes, including 4 up-hypomethylated oncogenes (CDC5L, MERTK, RHOA and YBX1) and 4 down-hypermethylated TSGs (BCR, DFFA, SCUBE2, TP63), were selected by PPI. Higher expression of methylated CDC5L-cg05671347, MERTK-cg08279316, RHOA-cg05657651 and YBX1-cg16306148, and lower expression of methylated BCR-cg25410636, DFFA-cg20696875, SCUBE2-cg19000089 and TP63-cg06520450, were associated with better overall survival (OS) in HCC patients. Multivariate analysis also showed they were independent prognostic factors for OS of HCC patients. Conclusions: In summary, different expression of methylated genes above mentioned were associated with better prognosis in HCC patients. Altering the methylation status of these genes may be a therapeutic target for HCC, but it should be further evaluated in clinical studies.

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“…Of note, among all of them we found some interesting genes related to hematologic diseases; 11 of these genes were downregulated after G-CSF mobilization (BCR, CASP3, CXCL2, EGR1, FOS, HIF1A, HOXA9, NFKBIA, NPM1, NUP98 and TXNIP) and three were up-regulated (AXL, EIF2AK2 and MAP4K1). BCR inhibits BCR-ABL oncogenic effects in chronic myeloid leukemia, 34 and it also participates in the regulation of cell cycle and gene expression. CASP3 plays an important role in apoptosis and it is used as a prognostic marker for hematologic diseases such as chronic myeloid leukemia and B-cell lymphoma.…”

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confidence: 99%

Granulocyte colony-stimulating factor produces long-term changes in gene and microRNA expression profiles in CD34+ cells from healthy donors

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o ngene and miRNA expression profiles in HPC from healthy donors, and to determine whether any changes in expression signatures persist in the long-term or return to the original status. Methods SamplesCD34 + progenitor cells from peripheral blood of six healthy donors were collected before and at 5, 30 and 365 days after the mobilization with G-CSF (mobilization regimen: 10-15 mg/kg of G-CSF daily for 5 days). All donors were included in the transplant program of the Hematology Department of the University Hospital Virgen del Rocío (Seville, Spain). The local ethics committee of the same hospital provided institutional review boardapproval for this study, and informed consent was obtained from all donors in accordance with the Declaration of Helsinki. Isolation of hematopoietic progenitor cellsMononuclear cells were collected from all samples by density gradient centrifugation with Ficoll-Paque solution (Amersham Biosciences, Uppsala, Sweden). The CD34 + cells were isolated in an AutoMACS pro separator (Miltenyi Biotec, Bergisch Gladbach, Germany) by positive immunomagnetic selection using the CD34 MACS microbead Human Kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and, after magnetic enrichment, CD34 + cells were sorted by flow cytometry. The purity of the isolated CD34 + cells was greater than 95% in all cases. RNA extractionTotal RNA was extracted by TRIsure (Bioline, Luckenwalde, Germany) in all samples. The quality and integrity of the RNA were verified by a Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA). MicroRNA and gene expressionThe expression profiles of 384 miRNA were analyzed in all samples using TaqMan Human MicroRNA v2.0 Arrays (Applied Biosystems, Foster City, CA. USA) which were analyzed on a 7900 HT Fast Real Time Polymerase Chain Reaction (PCR) System (Applied Biosystems, Foster City, CA, USA). The SDS 2.3 and RQ Manager 1.2 software (both Applied Biosystems, Foster City, CA, USA) were used for the analysis. Data were normalized using the average of the endogenous small-nucleolar RNU48 and the noncoding small nuclear U6, both included in the array.The expression profile of 45,000 genes was analyzed in the same samples using the Whole Human Genome Oligo microarray kit 4x44K (Agilent Technologies, Santa Clara, CA, USA). The microarrays were scanned in a GenePix reader (Molecular Devices, Sunnyvale, CA, USA). Samples from non-mobilized CD34 + cells were used as the reference group in both types of expression analysis.The expression of significant genes was validated by quantitative real-time PCR using Quantitec Primer Assays and the Quantitec SYBR Green Kit (both from Qiagen, Hilden, Germany) in a 7900 HT Fast Real Time PCR System (Applied Biosystems, Foster City, CA, USA). Data were normalized to the housekeeping gene ACTB and the group of samples from non-mobilized CD34 + cells was used as a control. The relative gene expression levels were calculated by the 2 -ΔΔCT method. Statistical analysisUnsupervised hierarchical clust...

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Kinase domain mutants of Bcr enhance Bcr-Abl oncogenic effects

Cited by 5 publications

References 18 publications

The Functional Interplay Between the t(9;22)-Associated Fusion Proteins BCR/ABL and ABL/BCR in Philadelphia Chromosome-Positive Acute Lymphatic Leukemia

The Functional Interplay Between the t(9;22)-Associated Fusion Proteins BCR/ABL and ABL/BCR in Philadelphia Chromosome-Positive Acute Lymphatic Leukemia

Prognostic value of aberrantly expressed methylation genes in human hepatocellular carcinoma

Granulocyte colony-stimulating factor produces long-term changes in gene and microRNA expression profiles in CD34+ cells from healthy donors

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