The MYC-YBX1 Circuit in Maintaining Stem-like Vincristine-Resistant Cells in Rhabdomyosarcoma
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ABSTRACT:
PROVIDER: PRJNA972687 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24564181.fastq.gz | Fastqsanger.gz | |||
| SRR24564182.fastq.gz | Fastqsanger.gz | |||
| SRR24564183.fastq.gz | Fastqsanger.gz |
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Project description:Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that causes significant devastation, with no effective therapy for relapsed disease. The mechanisms behind treatment failures are poorly understood. Our study showed that treatment of RMS cells with vincristine led to an increase in CD133-positive stem-like resistant cells. Single cell RNAseq analysis revealed that MYC and YBX1 were among the top-scoring transcription factors in CD133-high expressing cells. Targeting MYC and YBX1 using CRISPR/Cas9 reduced stem-like characteristics and viability of the vincristine-resistant cells. MYC and YBX1 showed mutual regulation, with MYC binding to the YBX1 promoter and YBX1 binding to MYC mRNA. The MYC inhibitor MYC361i synergized with vincristine to reduce tumor growth and stem-like cells in a zebrafish model of RMS. MYC and YBX expression showed a positive correlation in RMS patients, and high MYC expression correlated with poor survival. Targeting the MYC-YBX1 axis holds promise for improving survival in RMS patients.
2023-05-17 | GSE232536 | GEO
Project description: Not available
| S-EPMC10216535 | biostudies-literature
Project description:we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival but is dispensable for normal hematopoiesis. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 significantly induces apoptosis, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency promotes mRNA decay in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
2021-04-01 | GSE159152 | GEO
Project description:we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival but is dispensable for normal hematopoiesis. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 significantly induces apoptosis, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency promotes mRNA decay in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
2021-04-01 | GSE159153 | GEO
Project description:we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival but is dispensable for normal hematopoiesis. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 significantly induces apoptosis, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
2021-04-01 | GSE159178 | GEO
Project description:Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, with outcomes for relapsed or metastatic disease remaining poor, with 3-year survival rates below 30%. Despite aggressive multimodal therapy, no new effective treatments have been introduced for relapsed RMS in more than three decades, underscoring the urgent need to elucidate mechanisms of therapy resistance. We generated vincristine-resistant fusion-negative (FN) RMS cell lines through long-term dose escalation and identified enhanced MAPK pathway activation, evidenced by increased ERK phosphorylation in vitro and a major subset of post-chemotherapy patient tumor specimens. Pharmacologic MEK inhibition with trametinib or genetic suppression of MEK1 significantly impaired the growth of resistant cells and enhanced vincristine efficacy in a KRAS(G12D)-induced zebrafish FN RMS model, leading to reduced tumor burden and delayed relapse. Mechanistically, trametinib induced a senescence-associated cell-cycle arrest in resistant cells through a MYC–p21 regulatory axis, wherein MYC directly represses CDKN1A (p21) expression by binding to its promoter, and MYC depletion or trametinib-mediated MYC suppression result in p21 upregulation and senescence induction. Importantly, MYC overexpression rescued cells from trametinib-induced senescence, confirming its role in senescence bypass. Vincristine-resistant cells also exhibited increased dependence on the anti-apoptotic protein BCL-xL for survival, demonstrating heightened sensitivity to the selective BCL-xL inhibitor A-1155463. Accordingly, combined inhibition of MEK and BCL-xL using trametinib and A-1155463 significantly suppressed tumor growth and induced apoptosis in vincristine-resistant cells, producing significant antitumor activity in both cell line and zebrafish xenograft models of vincristine-resistant tumors. Collectively, these findings identify enhanced MAPK signaling and MEK/MYC/p21-mediated senescence bypass as key drivers of vincristine-resistant FN RMS and reveal a therapeutic vulnerability to combined MAPK and BCL-XL targeting, providing a rational therapeutic strategy and preclinical rationale for combination therapy in treatment-refractory RMS.
2026-03-24 | GSE325716 | GEO
Project description:Rhabdomyosarcoma (RMS) is a highly metastatic soft-tissue sarcoma that often develops resistance to current therapies, including vincristine. Since the existing treatments have not significantly improved survival, there is a critical need for new therapeutic approaches for RMS patients. FOXM1, a known oncogene, is highly expressed in RMS, and is associated with the worst prognosis in RMS patients. In the present study, we found that the combination treatment with specific FOXM1 inhibitor RCM1 and low doses of vincristine is more effective in increasing apoptosis and decreasing RMS cell proliferation in vitro compared to single drugs alone. Since RCM1 is highly hydrophobic, we developed innovative nanoparticle delivery system containing poly-beta-amino-esters and folic acid (NPFA), which efficiently delivers RCM1 to mouse RMS tumors in vivo. The combination of low doses of vincristine together with intravenous administration of NPFA nanoparticles containing RCM1 effectively reduced RMS tumor volumes, increased tumor cell death and decreased tumor cell proliferation in RMS tumors compared to RCM1 or vincristine alone. The combination therapy was non-toxic as demonstrated by liver metabolic panels using peripheral blood serum. Using RNA-seq of dissected RMS tumors, we identified Chac1 as a uniquely downregulated gene after the combination treatment. Knockdown of Chac1 in RMS cells in vitro recapitulated the effects of the combination therapy. Altogether, combination treatment with low doses of vincristine and nanoparticle delivery of FOXM1 inhibitor RCM1 in a pre-clinical model of RMS has superior anti-tumor effects and decreases CHAC1 while reducing vincristine toxicity
2023-01-18 | GSE223149 | GEO
Project description:In order to identify YBX1 binding sites on endogenous RNA, we performed HITS-CLIP on endogenous YBX1 We used a previously published method to perform HITS-CLIP on endogenous YBX1 (Licatalosi D, et al. 2008, Nature 456:464-U22)
2015-05-08 | E-GEOD-63604 | biostudies-arrayexpress
Project description:In order to identify YBX1 binding sites on tRNA fragments, we performed small-RNA HITS-CLIP on endogenous YBX1 We used a previously published method to perform HITS-CLIP on endogenous YBX1 (Chi SW, et al. 2009, Nature 460:479)
2015-05-08 | E-GEOD-63597 | biostudies-arrayexpress
Project description:YBX1 is a multifunctional protein involved in the control of transcription and translation. We identified YBX1 as an target of MEK/ERK signaling in colorectal cancer cell lines. We performed a ChIP-chip analysis of HCT116 cells to identify new potential target genes of YBX1. Comparison of input DNA fragments with fragments coprecipitated with YBX1 in HCT116 cells.
2010-10-09 | E-GEOD-18337 | biostudies-arrayexpress