Clinical and biological implications of target occupancy in chronic lymphocytic leukemia treated with acalabrutinib
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ABSTRACT:
PROVIDER: PRJNA562903 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10036600_1.fastq.gz | Fastqsanger.gz | |||
| SRR10036600_2.fastq.gz | Fastqsanger.gz | |||
| SRR10036601_1.fastq.gz | Fastqsanger.gz | |||
| SRR10036601_2.fastq.gz | Fastqsanger.gz | |||
| SRR10036602_1.fastq.gz | Fastqsanger.gz |
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Project description:Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in chronic lymphocytic leukemia (CLL). Target occupancy has been measured as a pharmacodynamic parameter in clinical studies of covalent BTK inhibitors. However, the kinetics of BTK turnover, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remains undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily or 200 mg once daily in 48 patients with relapsed/refractory or high-risk treatment naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% CI 78.9%, 99.9%) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI 70.0%, 97.8%) with twice daily dosing and an ORR of 79.2% (95% CI 57.9%, 92.9%) and an estimated PFS rate at 24 months of 87.2% (95% CI 57.2%, 96.7%) with once daily dosing. BTK resynthesis was faster in CLL than in healthy volunteers. Twice daily dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared to once daily dosing. Additional follow-up is required to address the impact of dosing schedule and BTK occupancy on long-term clinical outcomes.
2020-04-07 | GSE136634 | GEO
Project description:BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-?B pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.
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Project description:The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we conducted a genome-wide comparison of high-resolution nucleosome maps in peripheral-blood B cells from patients with chronic lymphocytic leukaemia (CLL) and healthy individuals at single base pair resolution. Our investigation uncovered significant changes of nucleosome positioning in CLL. Globally, the spacing between nucleosomes – the nucleosome repeat length (NRL) – was shortened in CLL. This effect was stronger in the more aggressive IGHV-unmutated than in the IGHV-mutated CLL subtype. Changes in nucleosome occupancy at specific sites were linked to active chromatin remodelling and reduced DNA methylation. Nucleosomes lost or gained in CLL marked differential binding of 3D chromatin organisers such as CTCF as well as immune response-related transcription factors and delineated mechanisms of epigenetic deregulation. The principal component analysis of nucleosome occupancy in cancer-specific regions allowed classification of samples between cancer subtypes and normal controls. Furthermore, patients could be better assigned to CLL subtypes according to differential nucleosome occupancy than based on DNA methylation or gene expression. Thus, nucleosome positioning constitutes a novel readout to dissect molecular mechanisms of disease progression and to stratify patients. Furthermore, we anticipate that the global nucleosome repositioning detected in our study, such as changes in the NRL, can be exploited for liquid biopsy applications based on cell-free DNA to monitor disease progression.
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Project description:In cancer patients, circulating endothelial cells (CEC) are increased and correlate with an aggressive course of the disease. However the clinical and biologic significance of CEC in chronic lymphocytic leukemia (CLL) is still uncertain. In this study we show that, in series of 171 CLL patients, CEC are increased in comparison to normal age and sex related controls. A higher level of CEC (> 20 ul) identifies a subset of patients with a more aggressive course of the disease characterized by a shorter time to first treatment both in univariate and multivariate analyses. CEC levels do not correlate with known markers of aggressiveness including stage, CD38 and ZAP70 positivity, and cytogenetics. By FISH analysis, in 7 cases a significant proportion of CEC presented the same cytogenetic lesion of neoplastic lymphocytes and immunophenotypic features of endothelial progenitor cells. The gene expression profile of sorted CEC showed a molecular pattern suggesting a derivation from CLL leukemic cells with increased cell survival and proliferation, diminished cell adhesion to extracellular matrix and enhanced pro-angiogenic function compared to their normal counterpart. These data suggest that in CLL, CEC are tumor-derived and may represent a new biologic marker of aggressiveness playing a role in disease evolution.
2010-03-01 | GSE14853 | GEO
Project description:This phase II trial studies how well giving lenalidomide with or without rituximab works in treating patients with progressive or relapsed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), or non-Hodgkin lymphoma (NHL). Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving lenalidomide together with or without rituximab may kill more cancer cells.
| 2111714 | ecrin-mdr-crc
Project description:The cellular origin of chronic lymphocytic leukemia (CLL) is debated. Transcriptome analysis of CLL and normal peripheral blood and splenic B cell subsets displayed highest similarity of CLL to mature CD5+ B cells. We identified a distinct CD5+CD27+ post-germinal center B cell subset, and revealed that immunoglobulin V gene mutated CLL are more similar to mutated CD5+ B cells, whereas unmutated CLL are more related to unmutated CD5+ B cells. Stereotyped immunoglobulin V gene rearrangements were significantly enriched among CD5+ B cells, providing further genetic evidence for a derivation of CLL from CD5+ B cells. Moreover, we identified deregulated expression patterns providing novel insights into the pathophysiology of CLL, including downregulation of EBF1 and KLF family members. Transcriptome profiling of CLL and healthy human blood and splenic mature B cell subsets. Identification of deregulated transcription patterns with implications on CLL pathobiology.
2012-09-27 | GSE36907 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant CD5+ B lymphocytes (CLL cells) in the peripheral blood, and their progressive infiltration in lymphoid organs. MMP-9 plays an important role in cell migration and survival, contributes to CLL pathogenesis by proteolytic and non-proteolytic mechanisms and may constitutive a therapeutic target. We used Affimetrix microarray technology to characterize the global gene expression profile of chronic lymphocytic leukemia (CLL) cells upon MMP-9 transfection. The aim was to establish whether MMP-9 regulates gene expression and to identify new therapeutic targets in CLL.
2016-03-21 | GSE78174 | GEO
Project description:We describe 9 CLL patients who underwent a spontaneous clinical regression. CD38 and ZAP-70 were negative in all cases. Immunoglobulin heavy chain variable region (IgVH) genes, mutated in all 7 evaluable patients, were restricted to the VH3 family in 6, with the usage of VH3-30 gene in 2. The light chain variable region genes were mutated in 6/8 cases, with the usage of Vκ4-1 gene in 3. Microarray analysis of CLL cells revealed a distinctive genomic profile. The number of activated T lymphocytes expressing IFN-γ, TNF-α and IL-4 was similar between CLL in spontaneous regression and healthy individuals.
2009-04-22 | GSE15777 | GEO
Project description:Recent data indicate that CD38, a cell surface enzyme and receptor, is part of the complex network of signals underlying the development, maintenance and progression of chronic lymphocytic leukemia (CLL). Here we show that CD38 signals directly facilitate short- (ERK1/2 phosphorylation) and long-term (chemotaxis) effects induced by CXCL12 exposure. Use of i) a specific enzyme inhibitor, ii) an agonistic anti-CD38 monoclonal antibody (mAb) and iii) microarray studies led to the conclusion that the receptor-like functions of CD38 are responsible for the observed effects. Interactions between CD38 and its non substrate ligand CD31 define a genetic signature characterized by modulation of a significant number of genetic pathways, involved in proliferation and migration. Blocking CD38 with domain-specific mAbs significantly lowers CXCL12 effects, in terms of ERK1/2 phosphorylation and chemotaxis. The molecular explanation behind the blocking activity of these mAbs lies in physical proximity between CD38 and the CXCL12 receptor CXCR4, as demonstrated by i) co-immunoprecipitation, ii) confocal microscopy and iii) direct measurement of CXCL12 binding to its receptor. Lastly, blocking anti-CD38 mAbs were successfully used in vivo to interfere with CLL cell recirculation from blood to the lymphoid organs, an event critically controlled by CXCL12. These results represent a first step towards the validation of anti-CD38 mAbs as potential therapeutics for certain CLL patients. Keywords: gene expression profiling by microarray, CLL, CD31, CD38
2009-12-22 | GSE14063 | GEO
Project description:B-cell chronic lymphocytic leukemia (B-CLL) shows an incredibly high heterogeneity in the clinical course, spanning from rapidly aggressive to completely indolent behaviour. In order to identify the correspondent gene expression variability, we investigated 29 cases of untreated B-CLL using microarray. Firstly, two robust CLL clusters were identified applying multiple unsupervised clustering algorithms. Their separation was mainly determined by the differential expression of several genes included into two gene groups designated OxPhos and Lyn clusters. OxPhos gene cluster, previously identified in a subset of diffuse large B-cell lymphomas, comprises genes coding for some respiratory chain enzymes, ribosomal proteins and translation factors. Moreover, increased levels of genes involved in the regulation of apoptosis and in the proteasome-ubiquitin complex and the down-regulation of LYN gene, member of B-cell receptor pathway, characterized the OxPhos CLL subset. These B-CLL biological clusters did not reveal any preferential distribution of Ig mutated or Ig unmutated CLL prognostic groups. Furthermore, we applied another unsupervised algorithm (Subtractive Unsupervised Analysis) after the exclusion of genes characterizing the previously identified CLL subsets. At this point, we could identify two new CLL clusters, showing a clear association to the Ig mutational status. In addition to the ZAP-70 and LPL genes, the patients with unmutated Ig expressed higher level of some interesting genes involved in B cell activation, cell cycle regulation, apoptosis resistance and angiogenesis. In conclusion, we showed that B-CLL is characterized by an intrinsic heterogeneity in gene expression pattern, which overcomes the influence of the immunoglobulin mutational status on B-cell chronic lymphocytic leukemia profiles. Keywords: chronic lymphocytic leukemia, gene expressione profile, immunuglobulin mutational status, clinical heterogeneity
2006-02-25 | GSE4207 | GEO