Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1048659 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27060700_1.fastq.gz | Fastqsanger.gz | |||
| SRR27060700_2.fastq.gz | Fastqsanger.gz | |||
| SRR27060701_1.fastq.gz | Fastqsanger.gz | |||
| SRR27060701_2.fastq.gz | Fastqsanger.gz | |||
| SRR27060702_1.fastq.gz | Fastqsanger.gz |
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Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR-ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR-ABL1 TKIs in CML.
2024-09-15 | GSE275701 | GEO
Project description:Although the development of tyrosine kinase inhibitors (TKIs), including BCR-ABL1 targeted therapies, rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast crisis (BC) progression remains a critical challenge. Here, we elucidate the significance of FLT3 signaling in the acquisition of drug resistance in BC-CML. Mechanistically, FLT3 expression in CML cells activated FLT3-JAK-STAT3-TAZ-TEAD-CD36 pathway, which conferred resistance to wide range of tyrosine kinase inhibitors (TKIs). Remarkably, a subgroup of BC-CML patients who expressed FLT3 showed strong correlation with the prognostic factors of CML independent of recurrent BCR-ABL1 mutations. We demonstrate that combining FLT3 inhibitors with BCR-ABL1 targeted therapies or single treatment with ponatinib can overcome drug resistance and promote cell death in patient-derived FLT3+ BC-CML cells and mouse xenograft models. Our findings reveal the mechanism of FLT3-mediated drug resistance in BC progression and suggest the inclusion of FLT3 as a therapeutic target for this defined group of patients.
2023-11-15 | GSE226360 | GEO
Project description:Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten CML patients. Accumulating evidence suggests that translational control is crucial for cancer development and progression. Here, we performed high throughput CRISPR/Cas9 screening and identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML-BC progression. PABPC1 preferentially improved the translation efficiency of multiple leukemogenic mRNAs with long and highly structured 5' untranslated regions, including BCR-ABL1 and its TKI-resistant mutants, through forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, but did not affect normal hematopoiesis seriously. More importantly, we identified two novel PABPC1 inhibitors, 1,10-Phen and ML324, which inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identified PABPC1 as a selective translation enhancing factor in CML-BC, the genetic or pharmacological inhibition of which overcame TKI resistance and suppressed BC progression in CML.
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Project description:Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten CML patients. Accumulating evidence suggests that translational control is crucial for cancer development and progression. Here, we performed high throughput CRISPR/Cas9 screening and identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML-BC progression. PABPC1 preferentially improved the translation efficiency of multiple leukemogenic mRNAs with long and highly structured 5' untranslated regions, including BCR-ABL1 and its TKI-resistant mutants, through forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, but did not affect normal hematopoiesis seriously. More importantly, we identified two novel PABPC1 inhibitors, 1,10-Phen and ML324, which inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identified PABPC1 as a selective translation enhancing factor in CML-BC, the genetic or pharmacological inhibition of which overcame TKI resistance and suppressed BC progression in CML.
2024-12-20 | GSE280879 | GEO
Project description:Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten CML patients. Accumulating evidence suggests that translational control is crucial for cancer development and progression. Here, we performed high throughput CRISPR/Cas9 screening and identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML-BC progression. PABPC1 preferentially improved the translation efficiency of multiple leukemogenic mRNAs with long and highly structured 5' untranslated regions, including BCR-ABL1 and its TKI-resistant mutants, through forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, but did not affect normal hematopoiesis seriously. More importantly, we identified two novel PABPC1 inhibitors, 1,10-Phen and ML324, which inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identified PABPC1 as a selective translation enhancing factor in CML-BC, the genetic or pharmacological inhibition of which overcame TKI resistance and suppressed BC progression in CML.
2024-12-20 | GSE280878 | GEO
Project description:Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten CML patients. Accumulating evidence suggests that translational control is crucial for cancer development and progression. Here, we performed high throughput CRISPR/Cas9 screening and identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML-BC progression. PABPC1 preferentially improved the translation efficiency of multiple leukemogenic mRNAs with long and highly structured 5' untranslated regions, including BCR-ABL1 and its TKI-resistant mutants, through forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, but did not affect normal hematopoiesis seriously. More importantly, we identified two novel PABPC1 inhibitors, 1,10-Phen and ML324, which inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identified PABPC1 as a selective translation enhancing factor in CML-BC, the genetic or pharmacological inhibition of which overcame TKI resistance and suppressed BC progression in CML.
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Project description:Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GAB2 as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transduced Gab2-/- bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors PI3K or SHP2. GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph+ hematologic neoplasms. RNA-Seq expression profiling of 6 mouse bone marrow samples: 3 GAB2 WT (+/+) and 3 GAB2 NULL (-/-)
2016-01-17 | E-GEOD-75615 | biostudies-arrayexpress
Project description:Prime editing-based resistance profiling of ABL1 variants against kinase inhibitors
| PRJNA1041071 | ENA
Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.
2017-06-06 | GSE99656 | GEO
Project description:Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GAB2 as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transduced Gab2-/- bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors PI3K or SHP2. GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph+ hematologic neoplasms.
2016-01-17 | GSE75615 | GEO