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Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

ABSTRACT: Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

PROVIDER: PRJNA633578 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11808549_1.fastq.gz	Fastqsanger.gz
	SRR11808549_2.fastq.gz	Fastqsanger.gz
	SRR11808550_1.fastq.gz	Fastqsanger.gz
	SRR11808550_2.fastq.gz	Fastqsanger.gz
	SRR11808551_1.fastq.gz	Fastqsanger.gz

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Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Project description:Ph+ acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors result in elevated expression of IL7R which enable the survival of transformed cells when IL7 was added together with the kinase inhibitors. Importantly, treatment with anti-IL7R antibodies prevents leukemia development in xenotransplantation models using patient-derived Ph+ ALL cells. Our results suggest that the association between IL7R and CXCR4 serves as molecular platform for BCR-ABL1 induced transformation and development of Ph+ ALL. Targeting this platform with anti-IL7R antibody eliminates Ph+ ALL cells including those with resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies may provide alternative treatment options for ALL in general and may suppress incurable drug-resistant leukemia forms.

2020-05-19 | GSE150784 | GEO

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Project description:Ph+ acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors results in elevated expression of IL7R which enables the survival of transformed cells when IL7 was added together with the kinase inhibitors. Importantly, treatment with anti-IL7R antibodies prevents leukemia development in xenotransplantation models using patient-derived Ph+ ALL cells. Our results suggest that the association between IL7R and CXCR4 serves as molecular platform for BCR-ABL1-induced transformation and development of Ph+ ALL. Targeting this platform with anti-IL7R antibody eliminates Ph+ ALL cells including those with resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies may provide alternative treatment options for ALL in general and may suppress incurable drug-resistant leukemia forms.

| S-EPMC7314847 | biostudies-literature

Geothlypis philadelphia

Project description:Geothlypis philadelphia

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Gene expression profiling in BCR/ABL expressing HSCs

Project description:The BCR-ABL oncogene, generated by Philadelphia chromosome, is present in about 95% human Chronic myeloid leukemia (CML) and 20~30% acute lymphoblastic leukemia (ALL). One of BCR-ABL isoforms, P210, is more often detected in CML and ALL patients. Although BCR-ABL kinase inhibitors are effective in controlling the diseases, they do not provide cure due to the development of drug resistance and the insensitivity of leukemia stem cells to these drugs. Identification of new therapeutic targets is critical. To identify potential target against leukemia stem cells, we studied gene expression in leukemia stem cells, which were identified in mice in our lab (Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S. 2006. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia. Proc Natl Acad Sci USA 103(45):16870-16875.). The sorted leukemia stem cells that expressed BCR-ABL were used for isolation of RNA, followed by the analysis of gene expression using the DNA microarray. The same lineage of non-BCR-ABL-expressing normal hematopoietic stem cells was used as control. We have identified some interesting genes that are up- or down-regulated by BCR-ABL in these leukemia stem cells. We are currently studying the functions of these identified genes. Keywords: Genetic modification

2008-03-22 | GSE10912 | GEO

A Tumor Suppressor Function of LncRNA-X in Bcr-Abl-induced Tumorigenesis

Project description:Aberrant long noncoding RNA (lncRNA) expression has been described in many human malignancies, including leukemia. Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) is a stem cell disease induced by Bcr-Abl hybrid gene. Here we attempt to identify lncRNAs associated with CML by analyzing lncRNA expression profiles in K562 cells when Bcr-Abl gene silenced. LncRNA microarray analysis revealed a group of lncRNAs that exhibit Bcr-Abl-dependent expression. In this study, we focused on lncRNA-X that was downregulated by Bcr-Abl, suggesting that lncRNA-X might have a function of tumor suppression. We showed that lncRNA-X over-expression delays Bcr-Abl-induced tumorigenesis in vivo, maybe through its effect on cell survival by modulating STAT5-dependent expression of anti-apoptotic Bcl-XL protein. We also demonstrated that lncRNA-X may affect tumor formation behavior of Bcr-Abl-transformed cells by regulating signaling pathways associated with leukemia stem cells of CML. Together, these results suggest that lncRNA-X suppresses Bcr-Abl-induced tumorigenesis, and the tumor suppressor function of lncRNA-X may be of significance for exploring novel therapeutic strategies for treating CML. This microarray was performed to identify lncRNAs associated with Bcr-Abl-induced chronic myeloid leukemia (CML).

2015-07-20 | GSE42269 | GEO

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Project description:plant-microbial synergism Metagenome

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pre-B cells from normal control, preleukemic, fully leukemic and fully leukemic, nilotinib-treated P190 BCR/ABL transgenic mice

Project description:Precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) can be subdivided into different categories based on genetic abnormalities. One type of pre-B ALL is characterized by the presence of the Philadelphia (Ph) chromosome, the derivative chromosome 22 that is one product of a reciprocal translocation between chromosomes 22 and 9. The 22/9 translocation fuses the 5’ part of the BCR gene to the 3’ end of the c-ABL gene. The resulting BCR/ABL fusion encodes a Bcr/Abl protein with deregulated Abl kinase activity. Two major fusion proteins are found in Ph-positive leukemias which differ in molecular weight and the size of the Bcr moiety. The P190 Bcr/Abl protein is common in Ph-positive ALL. Targeted tyrosine kinase inhibitors such as nilotinib are used therapeutically to treat this type of leukemia. The 22/9 translocation fuses the 5’ part of the BCR gene to the 3’ end of the c-ABL gene. The resulting BCR/ABL fusion encodes a Bcr/Abl protein with deregulated Abl kinase activity. Two major fusion proteins are found in Ph-positive leukemias which differ in molecular weight and the size of the Bcr moiety. The P190 Bcr/Abl protein is common in Ph-positive ALL. Targeted tyrosine kinase inhibitors such as nilotinib are used therapeutically to treat this type of leukemia.

2018-02-05 | GSE110104 | GEO

Gene expression profiling of IL7R+PIR+ and IL7R-PIR- subsets in LIN-c-Kit+ E12.5 mouse fetal liver cells

Project description:In order to find out taget genes of Runx/Cbfb2 complexes in PIR+IL7R+ subset. In particular, genes that would explain why the size of thymus was small by lack of Cbfb2. Upon finding of decresed IL7R+PIR+ subset, which was reported as thymus-homing progenitor, in Cbfb2 deficient embruos embryos, we focused on these population.

2017-12-05 | GSE86850 | GEO

Gene expression pattern in CXCR4+ and CXCR4- subpopulation of breast cancer cells

Project description:The goal of this study was to identify signalling molecules downstream of CXCR4 in breast cancer cells. For this purpose, we sorted CXCR4-positive and CXCR4-negative cells from MDA-MB-231 breast cancer cell line by flow cytometry and performed microarrays analysis. Three sets of samples, each in quadruplicate, were analyzed. These include CXCR4-positive subpopulation, CXCR4-positive subpopulation treated with SDF-1 (ligand for CXCR4, also called CXCL12) for one hour and CXCR4-negative subpopulation.

2010-04-28 | E-GEOD-15893 | biostudies-arrayexpress

Functional proteomics defines differential signaling networks of the oncogenic kinases Bcr-Abl p210 and p185

Project description:The two major isoforms of the oncogenic Bcr-Abl tyrosine kinase, p210 and p185, are expressed upon the Philadelphia chromosome translocation. p210 is the hallmark of chronic myelogenous leukemia, whereas p185 occurs in the majority of B-cell acute lymphoblastic leukemia. Differences in protein-protein interactions and activated signaling pathways that may be associated with the different diseases driven by p210 and p185 are unknown. We have performed a quantitative comparative proteomics study of p210 and p185 and found strong differences in the interactome and phosphoproteome. Whereas the AP2 endocytosis complex interacts preferentially with p185, the phosphatase Sts1 is enriched with p210. Stronger activation of STAT5 and ERK1/2 is observed with p210, whereas Lyn is activated by p185. These results were validated in human p210 and p185-positive cell lines. Our findings contribute to a more coherent understanding of Bcr-Abl signaling, mechanisms of oncogenic transformation, resulting disease pathobiology and responses to kinase inhibitors.

2017-01-31 | PXD005149 | Pride

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