Expression data from AML cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59808 | GEO | 2014/07/29
SECONDARY ACCESSION(S): PRJNA256300
REPOSITORIES: GEO
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Project description:Post-chemotherapy relapse presents a major unmet medical need in AML where treatment options are limited. We used gene expression profile from 32 AML cell lines to characterize expression difference between responder and non-responders to PIM inhibitors. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. All AML cell lines were purchased from either ATCC or DSMZ and cultured accordingly to vendorsM-bM-^@M-^Y protocols. Gene expression were measured from the cell lines using Affymetrix microarrays. Response to PIM inhibitors (IC50) was recorded for each cell line, and association between drug response and gene expression were analyzed.
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Project description:PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity in inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.
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Project description:Many studies have shown association of tumor infiltrating B-cells and presence of tertiary lymphoid structure with improved clinical responses to immune checkpoint inhibitors therapy. We hypothesized that their presence could also have an impact on TIL therapy response. To address this, we performed RNA-seq of FFPE samples from a cohort of patients that received TIL therapy. Melanoma tumors collected prior to TIL infusion were evaluated for immune content in 9 responders and 11 non-responders to TIL therapy. Our data demonstrate an increase in class-switched memory B-cells in responders compared with non-responders to TIL therapy. In the myeloid compartment, increased presence of dendritic cell populations (pDC, aDC, and iDC) and basophils was observed in responders to TIL therapy, as well as higher content of γδ T cells and effector memory CD8+ T cells (CD8+ Tem) in the T-cell compartment. Next, we assessed the TLS presence in the same cohort by a gene expression signature of 12 chemokines using principal component analysis. The responders showed a higher TLS score compared with the non-responder patients, suggesting that patients responding to TIL therapy had more TLS in their tumors than the non-responder patients. These observations indicate that, same as in the immune checkpoint inhibitors therapy response, presence of B-cells and TLS might have a positive impact in the clinical outcome to TIL therapy.
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Project description:The transcription factors STAT5A and STAT5B are essential downstream mediators of many tyrosine kinases, particularly in hematopoietic cancers. As such, STAT5 is activated by FLT3-ITD, which is a constitutively active tyrosine kinase driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 function is of significant clinical value. Here, we describe the novel small molecular weight inhibitor AC-4-130 that directly binds to the phosphotyrosine (pY)-binding pocket of the STAT5 SH2 domain, thereby disrupting STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent induction of gene transcription. AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Importantly, AC-4-130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. In summary, we report the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor that can efficiently block pathological levels of STAT5 activity in AML. The synergistic effects of AC-4-130 tyrosine kinase inhibitors as well as emerging treatment strategies provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.
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Project description:As a direct consequence of the high diversity of the aggressive blood cancer acute myeloid leukemia (AML), proteomic samples from patients are strongly heterogeneous, rendering their accurate relative quantification challenging. In the present study, we investigated the benefits of using a super-SILAC mix of AML derived cell lines as internal standard for quantitative shotgun studies. The Molm-13, NB4, MV4-11, THP-1, and OCI-AML3 cell lines were selected for their complementarity with regard to clinical, cytogenetic and molecular risk factors used for prognostication of AML patients. The resulting internal standard presents a high coverage of the AML proteome compared to single cell lines allied with high technical reproducibility, thus enabling its use for AML patient comparison. This was confirmed by comparing the protein regulation between the five cell lines and applying the internal standard to patient material.
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Project description:To determine the immune mechanism of anti-PD1 therapy, we carried out an anti-PD1 treatment on C57 BL/6J mice bearing mouse bladder urothelial carcinoma with three gene knockout. Anti-PD-1 immunotherapy resulted in a mixed pattern of treatment responses in individual tumors. Then, we performed single cell transcriptome profiling for tumor xenografts from Control IgG, anti-PD-1 non-responders and anti-PD-1 responders group. Duplicate tumors in each group were mixed and sequenced together as one representative sample. In results, we captured 4762 cells from Control IgG group, 4459 cells from anti-PD-1 non-responders group and 4861 cells from anti-PD-1 responders group. identified 8 clusters of immune cells in treated samples (basophils, B cells, dendritic cells, macrophages, monocytes, neutrophils, NK cells, and T cells). Responder xenografts displayed significantly increased immune cell infiltration (15.2%, 742 immune cells / 4861 total cells) compared to the non-responder tumors (10.1%, 452 immune cells/ 4459 total cells, Fisher Exact Test p<0.0001). Specifically, there were more T cells (46/4861 vs 18 /4459, p=0.002), and macrophages (420/4861 vs 287/4459, p=0.002) in responder xenografts than in non-responder xenografts. Compared to control IgG tumors, response tumors exhibited an immune-inflamed phenotype with significant infiltration of T cells and NKT cells, whereas non-responder tumors showed no significant change. The higher percentage of T cells and macrophages tumor infiltration in responders suggests a potential role of innate immune microenvironment for the Immune checkpoint inhibitor (ICI) treatment response. This study provides the insights of immune environments in ICI-treated bladder tumor xenograft on C57 mice.
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Project description:The study uses RNA sequencing to profile AZD1208 resistant (AZDR) vs AZD1208 sensitive HSB-2 cells. PIM inhibitor treatment decreases leukemia burden in early T-cell precursor acute lymphoblastic leukemias (ETP-ALL) both in vitro and in vivo. However, prolonged treatment of ETP-ALL with PIM kinase inhibitors results in PIM inhibitor resistance. The analysis revealed that the HOXA9, mTOR, MYC, NF-B, and PI3K-AKT pathways were activated in PIM inhibitor resistant ETP-ALL
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Project description:IDH mutations are found in 20% of acute myeloid leukemia (AML) patients. IDH inhibitors (IDHi) have emerged as a novel treatment option. However, only 30-40% of patients respond to single drug treatment and there is an unmet need for improvement as well as identifying alternative treatment options. The overall aim of this study was therefore to gain deeper insights into the molecular signatures of IDH mutations, the effects of IDHi as well as to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. Here, we have characterized the transcriptional and epigenetic landscape before and after treatment with IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts. We discovered decreased DNA hydroxymethylation in IDH2 mutated AML cells, particular in enhancers and a perturbed transcriptional regulatory network involving myeloid transcription factors. In addition, hypermethylation of the HLA I cluster caused a dramatic down-regulation of HLA genes, triggering an enhanced natural killer (NK) cell activation, and displayed an increased susceptibility to NK cell mediated killing. These responses were reverted when the AML cells were pre-exposed to IFN-gamma, resulting in up-regulation of cell surface HLA class I. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders continued to harbor hypermethylation in HLA class I genes, suggesting maintained susceptibility to NK cells. In conclusion, this study provides new insights into the perturbed epigenetic and transcriptional regulation in IDH mutated AML and shed light on a potential strategy for personalized medicine in AML.
2023-07-09 | GSE207830 | GEO
Project description:IDH mutations are found in 20% of acute myeloid leukemia (AML) patients. IDH inhibitors (IDHi) have emerged as a novel treatment option. However, only 30-40% of patients respond to single drug treatment and there is an unmet need for improvement as well as identifying alternative treatment options. The overall aim of this study was therefore to gain deeper insights into the molecular signatures of IDH mutations, the effects of IDHi as well as to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. Here, we have characterized the transcriptional and epigenetic landscape before and after treatment with IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts. We discovered decreased DNA hydroxymethylation in IDH2 mutated AML cells, particular in enhancers and a perturbed transcriptional regulatory network involving myeloid transcription factors. In addition, hypermethylation of the HLA I cluster caused a dramatic down-regulation of HLA genes, triggering an enhanced natural killer (NK) cell activation, and displayed an increased susceptibility to NK cell mediated killing. These responses were reverted when the AML cells were pre-exposed to IFN-gamma, resulting in up-regulation of cell surface HLA class I. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders continued to harbor hypermethylation in HLA class I genes, suggesting maintained susceptibility to NK cells. In conclusion, this study provides new insights into the perturbed epigenetic and transcriptional regulation in IDH mutated AML and shed light on a potential strategy for personalized medicine in AML. Methylation/hydroxymethylation profiling by array
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