CLL-Venetoclax
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB24344 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2239978.fastq.gz | Fastqsanger.gz | |||
| ERR2242430.fastq.gz | Fastqsanger.gz | |||
| ERR2242430_1.fastq.gz | Fastqsanger.gz | |||
| ERR2242430_2.fastq.gz | Fastqsanger.gz | |||
| ERR2242440.fastq.gz | Fastqsanger.gz |
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Project description:Anti-leukemic treatment in chronic lymphocytic leukemia (CLL) impacts autologous T cells through various direct and indirect mechanisms. However, how first-line treatment with venetoclax and obinutuzumab impacts the TRB repertoire has not been studied. Here, we have used next-generation sequencing to longitudinally characterize the TRB repertoire of previously untreated CLL patients who received treatment with obinutuzumab and venetoclax in the HOVON-139/ GIVE trial. Following treatment, due to the emergence of a polyclonal population of small-sized, diverse clonotypes, TRB repertoire diversity increased (Shannon’s H; trial entry 5.5 [95%CI 5.2-6.2] vs end of induction treatment [EOiT] 6.2 [95%CI 5.7- 6.7], P=0.001). In contrast, treatment with obinutuzumab and venetoclax did not ameliorate TRB oligoclonality (EOiT, cumulative frequency of top 10 clonotypes 32.5% [95%CI 25.3-39.9], P=0.10; R+12 CF10 31.2% [95%CI 24.3-38.1], P=0.17), due to the persistence of large pre-treatment clonotypes. Patients with IGLV3-21R110 CLL had weaker recovery of TRB repertoire diversity (mean Shannon’s H 5.2 [95%CI 4.0-6.3] vs 6.8 [95%CI 6.3-7.3], P=0.01). TRB clonotypes that were shared among patients could be identified, a minority of which had known pathogenic or auto-antigenic affinity. The concurrent presence or future resurgence of MRD did not impact the TRB repertoire, but low TRB diversity (Poisson regression coefficient -0.32±0.15, P=0.046) and high oligoclonality (Poisson regression coefficient 0.02±0.009, P=0.02) were associated with an increased risk of infection. These data provide the groundwork for the future investigation of the fitness of autologous T cells for T cell-mediated immunotherapy, following treatment with obinutuzumab and venetoclax.
2024-12-18 | GSE268787 | GEO
Project description:In chronic lymphocytic leukemia, measurable residual disease (MRD) depth following fixed-duration treatment is associated with progression-free survival (PFS). Often, MRD is reported as a static parameter, but successive MRD measurements may more accurately capture MRD dynamics and reveal valuable prognostic information. We used our recently developed IGHV leader-based NGS assay to measure MRD at four timepoints in 60 patients treated in the HOVON-139/GIVE trial, in which previously untreated patients received one year induction treatment with obinutuzumab and venetoclax, followed by randomization to consolidation treatment with venetoclax or MRD-conditional consolidation. Induction treatment resulted in MRD undetectability (<10-5) in 93% of assessed patients, with 85% and 74% of patients retaining MRD undetectability at six and twelve months after randomization. Uniquely, we measured MRD at a very early timepoint, during the fourth week of venetoclax ramp-up after obinutuzumab pre-induction. Here, MRD levels showed large interindividual variation, and, importantly, were associated with the probability of achieving MRD undetectability after induction treatment, MRD conversion after randomization and PFS. Additionally, the IGHV leader-based NGS assay allows characterization of the healthy background IGHV repertoire. Of note, venetoclax consolidation treatment, compared to no consolidation treatment, significantly impaired polyclonal IGHV repertoire reconstitution after induction treatment with venetoclax and obinituzumab.
2024-03-01 | GSE225043 | GEO
Project description:Guieze R, Liu VM, Rosebrock D, Jourdain AA, Hernandez-Sanchez M, Martinez A, Sun J, Baranowski K, Thompson PA, Heo J, Cartun Z, Aygun O, Notarangelo G, Livitz D, Li S, Hacken ET, Davids MS, Iorgelescu JB, Zhang W, Biran A, Fernandes SM, Brown JR, Ana Lako A, Ciantra ZB, Keskin DB, Udeshi ND, Wierda WG, Livak KJ, Letai AG, Neuberg D, Harper JW, Carr SA, Piccioni F, Ott CJ, Leshchiner I, Johannessen CM, Doench J, Mootha VK, Getz G, Wu CJ. 2019. Mitochondrial apoptosis can now be targeted in lymphoid malignancies with the first FDA-approved B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that resistance to venetoclax in patients with chronic lymphocytic leukemia is associated with marked and complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members. Systematic analyses of patient samples and cell lines confirmed MCL-1 overexpression and AMPK activation as underlying mechanisms for venetoclax resistance. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.
2019-03-02 | MSV000083512 | MassIVE
Project description:High Expression Level of ROR1 and ROR1-signaling Associates With Venetoclax Resistance In Chronic Lymphocytic Leukemia
| PRJNA792609 | ENA
Project description:Genomic profiles of CLL (Chronic Lymphocytic Leukemia) patients. 11 CLL patients were selected for detection of genomic aberrations, 8 patients with atypical CLL and 3 patients with typical CLL.
2009-12-16 | GSE19458 | GEO
Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.
2019-05-03 | GSE125403 | GEO
Project description:Early measurable residual disease dynamics and B cell receptor reconstitution following venetoclax and obinutuzumab in chronic lymphocytic leukemia
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Project description:Genomic profiles of CLL (Chronic Lymphocytic Leukemia) patients. 11 CLL patients were selected for detection of genomic aberrations, 8 patients with atypical CLL and 3 patients with typical CLL. Patient's DNA were hybridized against Promega control on Agilent G4410A arrays and scanned with the Agilent G2505B scanner.
2010-05-18 | E-GEOD-19458 | biostudies-arrayexpress
Project description:To identify a novel circRNA which could serve as a plasma biomarker and explore its function and molecular mechanism as well as clinical significance in chronic lymphocytic leukemia (CLL) we performed circRNA microarray analysis.
2021-03-11 | GSE131469 | GEO
Project description:Determinants of venetoclax resistance
| PRJNA558091 | ENA