Genome-Wide CRISPR-Cas9 Screening Identifies a Synergy between Hypomethylating Agents and SUMOylation Blockade in Myelodysplastic Syndromes and Acute Myeloid Leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE261339 | GEO | 2024/07/24
REPOSITORIES: GEO
Similar Datasets
Project description:Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS). However, acquired resistance and treatment failure are hallmarks of HMA therapy. Developing effective and rational HMA-focused combinatorial therapies is challenging as the underlying mechanisms driving HMA efficacy are complex. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and characterized TOPORS as a highly ranked target that synergizes with HMAs to reduce leukemic burden and improve survival in xenograft models. We demonstrated that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation demonstrates a favourable therapeutic index and represents a rational framework towards the treatment of High-Risk MDS (HR-MDS) or Acute Myeloid Leukemia (AML).
2024-07-25 | PXD050539 | Pride
Project description:Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS). However, acquired resistance and treatment failure are hallmarks of HMA therapy. Developing effective and rational HMA-focused combinatorial therapies is challenging as the underlying mechanisms driving HMA efficacy are complex. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and characterized TOPORS as a highly ranked target that synergizes with HMAs to reduce leukemic burden and improve survival in xenograft models. We demonstrated that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation demonstrates a favourable therapeutic index and represents a rational framework towards the treatment of High-Risk MDS (HR-MDS) or Acute Myeloid Leukemia (AML).
2024-07-24 | GSE261338 | GEO
Project description:Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS). However, acquired resistance and treatment failure are hallmarks of HMA therapy. Developing effective and rational HMA-focused combinatorial therapies is challenging as the underlying mechanisms driving HMA efficacy are complex. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and characterized TOPORS as a highly ranked target that synergizes with HMAs to reduce leukemic burden and improve survival in xenograft models. We demonstrated that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation demonstrates a favourable therapeutic index and represents a rational framework towards the treatment of High-Risk MDS (HR-MDS) or Acute Myeloid Leukemia (AML).
2024-07-24 | GSE261337 | GEO
Project description:Although hypomethylating agents (HMAs) significantly improve outcomes in myelodysplastic syndromes (MDS), only half the patients achieve objective responses, and most responders lose response within 1-2 years. Azacitidine prolongs survival by a median of only 9.5 months. Failure of HMA therapy is associated with a very dismal prognosis. Therefore, novel therapeutic approaches are clearly needed.The sequential use of the alternative HMA after failure of first line HMA is associated with modest efficacy. The improved understanding of the biologic underpinnings of the disease have opened the door to study investigational agents that target disrupted molecular pathways critical to the pathogenesis of MDS. Combination treatment strategies using an azacitidine backbone are demonstrating promising early results. Expanding the applicability of allogeneic stem cell transplantation (alloSCT), the only curative modality, by reducing toxicity and relapse rates is another area of active research.Sequential switching to the alternative HMA, clinical trials of novel targeted therapies, azacitidine-based combination therapeutic strategies, and improvements in the alloSCT platform are the main directions in improving outcomes of MDS post HMA failure.
| S-EPMC4124617 | biostudies-literature
Project description:Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndrome (MDS). However, only around 50% of patients respond to these agents, and responses tend to be transient, with loss of response frequently happening within 2 years and being associated with very poor prognosis and limited therapeutic options. Identification of patients who will respond to HMAs is challenging. Mechanisms underlying resistance to HMAs are not clear yet. Recently, absence of response has been associated with increased cell-cycle quiescence among the hematopoietic progenitor cells. There are no standard-of-care options for patients after HMA failure. However, the increasing knowledge of MDS pathogenesis has led to the development of new potential therapies, including HMAs with longer half-life and exposure, inhibition of the antiapoptotic BCL2 protein with venetoclax or inhibition of immune-checkpoint regulatory proteins such as PD-1 or CTLA-4, innate immunity and targeting of CD33/CD3 with multiple monoclonal antibodies. In addition, multiple targeted agents are opening opportunities to treat subgroups of patients whose disease harbors mutations in TP53, IDH, FLT3, and genes involved in splicing machinery. Newer formulations of intensive chemotherapy and its different combinations may be considered a valid option in selected patients after HMA failure. Finally, decision making at the time of failure of response to HMAs should be personalized, taking into account that allogenic stem-cell transplantation remains the only therapeutic approach with curative potential in these patients. In the current review, we will focus on all the above aspects.
| S-EPMC6515843 | biostudies-literature
Project description:We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P <0.001). Further, TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed.
| S-EPMC4924706 | biostudies-literature
Project description:Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4+ and CD8+ T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.
| S-EPMC7947882 | biostudies-literature
Project description:Hypomethylating agents (HMAs) are widely used in the treatment of myelodysplastic syndromes (MDSs), yet identifying those patients unlikely to benefit remains challenging. We assessed response and overall survival (OS) in 247 patients molecularly profiled by next-generation sequencing (NGS) before first-line HMA therapy, and a subset of 108 patients were sequenced serially during treatment. The most common mutations included TP53 (33.1%), ASXL1 (19%), TET2 (16.5%), DNMT3A (14.1%), and SRSF2 (12.1%). The overall response rate was 42.1%, with the composite TET2-mutant/ASXL1 wild-type genotype representing the strongest predictor of response (overall response rate, 62.1%; complete remission rate, 34.5%). The median OS for the cohort was 15 months, and the number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02), as well as mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were identified as independent covariates associated with inferior OS in multivariable analysis. Serial molecular profiling revealed that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic hematopoietic cell transplantation. These data support baseline molecular profiling by NGS in MDS patients treated with HMAs and provide novel observations of sequential profiling during therapy that provide particular value in TP53-mutated disease.
| S-EPMC7903224 | biostudies-literature
Project description:Hypomethylating agents (HMA) have played a pivotal role for treating myelodysplastic syndromes (MDS) over the past decade, inducing sustained hematological responses and delaying progression to leukemia. However, a vast majority of patients will experience treatment failure within 2 years, with poor prognoses and limited options, and management of this growing patient population remains unclear. Areas covered: With the introduction of new agents in the MDS field, a better understanding of the biology of MDS, and updated information on standard of care options (including allogeneic transplantation), we re-evaluate the global treatment strategy in MDS via novel agents, focusing in particular on investigational approaches for patients who fail to respond to HMA when applicable. This review aims to address two questions: what are reasonable alternatives to HMA in MDS, and what strategies can be used for patients experiencing HMA failure. Expert opinion/commentary: HMA therapy remains a mainstay of treatment, even if additional research is still warranted to maximize its benefits for the different groups of patients. The outcome of patients experiencing HMA failure remains grim, without standard of care, but several new approaches seem promising, as there is an increasing focus on studying treatments for patients refractory to HMA treatment.
| S-EPMC6121132 | biostudies-literature
Project description:Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clinical trials of decitabine and azacitidine used alone and in combination with other chemotherapeutics demonstrated their capacity to treat hematological malignancies and prolong the survival of MDS and AML patients. Although phase III clinical trials examining bortezomib's role in MDS and AML patients are limited, its underlying mechanisms in MM highlight its potential as a chemotherapeutic for such malignancies. Further research is needed to better understand how the epigenetic mechanisms mediated by these chemotherapeutic agents and their targeted gene networks are associated with the development and progression of MDS into AML. This review discusses the mechanisms by which decitabine, azacitidine, and bortezomib alter epigenetic programs and their results from phase III clinical trials.
| S-EPMC8308509 | biostudies-literature