Ontology highlight
ABSTRACT:
PROVIDER: PRJNA717917 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14086358_1.fastq.gz | Fastqsanger.gz | |||
| SRR14086358_2.fastq.gz | Fastqsanger.gz | |||
| SRR14086359_1.fastq.gz | Fastqsanger.gz | |||
| SRR14086359_2.fastq.gz | Fastqsanger.gz | |||
| SRR14086360_1.fastq.gz | Fastqsanger.gz |
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Project description:G3BP2-KIT drives leukemia amenable to kinase inhibition in Ph-like ALL: RNAseq for human sample
| EGAD00001007564 | EGA
Project description:Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted
| EGAS00001000654 | EGA
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. In this study, the tyrosine kinase inhibitor imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of Ph+ ALL cell lines were analyzed in response to imatinib treatment.
2010-09-10 | GSE23743 | GEO
Project description:Acute Myeloid Leukemia (AML) is the most common and aggressive form of acute leukemia, with a 5-year survival rate of just 24%. Over a third of all AML patients harbor activating mutations in kinases, such as the receptor tyrosine kinases FLT3 and KIT. FLT3 and KIT mutations are associated with poor clinical outcomes and lower remission rates in response to standard-of-care chemotherapy. We have recently identified that the core kinase of the non-homologous end joining DNA repair pathway, DNA-PK, is activated downstream of FLT3; and targeting DNA-PK sensitized FLT3-mutant AML cells to standard-of-care therapies. Herein, we investigated DNA-PK as a possible therapeutic vulnerability in KIT mutant AML, using isogenic FDC-P1 myeloid progenitor cell lines transduced with an empty vector or oncogenic mutant KIT (V560G, D816V). Targeted quantitative phosphoproteomic profiling identified phosphorylation of DNA-PK at threonine 2599 in KIT mutant cells, indicative of DNA-PK activation. Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared to empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling via using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death. Discovery phosphoproteomic analysis of KIT-D816V cells revealed that dasatinib single-agent treatment inhibited ERK1 activity, and M3814 single-agent treatment inhibited Akt/mTOR activity. The combination of dasatinib and M3814 treatment inhibited both ERK/MAPK and Akt/mTOR activity, and induced synergistic inhibition of phosphorylation of transcription regulators including MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair, and demonstrates that DNA-PK is a promising novel therapeutic target for KIT mutant cancers.
2023-01-26 | PXD030214 | panorama
Project description:The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Acute lymphoblastic leukemia (ALL) cells are derived from B cell precursors in most cases and typically carry rearranged immunglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph-positive ALLs as compared to 6 of 80 Ph-negative ALLs. Forced expression of BCR-ABL1 in Ph-negative ALL cells and inhibition of the BCR-ABL1-kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph-positive ALL, IGH V region genes and BCL6 were mutated in many Ph-positive but unmutated in most Ph-negative cases. In addition, AID introduced DNA-single-strand breaks within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset. Keywords: gene expression array-based (RNA / in situ oligonucleotide)
2007-04-03 | GSE7182 | GEO
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. In this study, the tyrosine kinase inhibitor imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of Ph+ ALL cell lines were analyzed in response to imatinib treatment. Four Ph+ ALL cell lines (BV-173, NALM-1, SUP-B15, and TOM1) were either treated with 10µM STI571 (Imatinib) for 16 hours or cultured in absence of STI571.
2010-09-10 | E-GEOD-23743 | biostudies-arrayexpress
Project description:The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Acute lymphoblastic leukemia (ALL) cells are derived from B cell precursors in most cases and typically carry rearranged immunglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph-positive ALLs as compared to 6 of 80 Ph-negative ALLs. Forced expression of BCR-ABL1 in Ph-negative ALL cells and inhibition of the BCR-ABL1-kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph-positive ALL, IGH V region genes and BCL6 were mutated in many Ph-positive but unmutated in most Ph-negative cases. In addition, AID introduced DNA-single-strand breaks within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset. Experiment Overall Design: To study the gene expression profile of two Ph-positive ALL cell lines (BV173 and SUP-B15) in the presence or absence of 10 μmol/l STI571 for 16 hours
2008-06-15 | E-GEOD-7182 | biostudies-arrayexpress
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which is present in almost every patient with chronic myeloid leukemia. In this study, the tyrosine kinase inhibitor Imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of CML cell lines were analyzed in response to Imatinib treatment.
2010-10-10 | GSE24493 | GEO
Project description:Targeting the MAPK signaling is an effective therapeutic approach in acute myeloid leukemia (AML) with mutations in FLT3 and KIT tyrosine kinase receptors. SHP2 is a central node in the MAPK signaling pathway and SHP2 inhibition was shown to supress leukemia proliferation in vitro and in vivo. In order to investigate the gene expression alterations induced by allosteric SHP2 inhibition and identify potential co-targets for pharmacological inhibition, we treated three human FLT3 and KIT mutant AML cell lines with RMC-4550 and performed RNAseq.
2022-11-08 | GSE217359 | GEO
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