Immunotherapeutic targeting of surfaceome heterogeneity in AML
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ABSTRACT:
PROVIDER: PRJNA1010863 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy remains underexploited in AML compared to other hematological malignancies. Currently, gemtuzumab ozogamicin is the only therapeutic antibody approved for this disease. To identify potential targets for immunotherapeutic intervention, we analyzed the surface proteome of 100 genetically diverse primary human AML specimens for the identification of cell surface proteins and conducted single-cell transcriptome analysis on a subset of these specimens to assess antigen expression at the sub-population level. Through this comprehensive effort, we successfully identified numerous antigens and markers preferentially expressed by primitive AML cells. Many identified antigens are targeted by therapeutic antibodies currently under clinical evaluation for various cancer types, highlighting the potential therapeutic value of the approach. Importantly, this initiative led to the uncovering of AML heterogeneity at the surfaceome level, identifying several antigens and potential LSC markers characterising AML subgroups and positioning immunotherapy as a promising approach to target AML subgroup specificities.
2024-05-21 | GSE241989 | GEO
Project description:We exploited the extensive genomic diversity of the Leucegene cohort of primary human AML specimens to provide an overview of the human AML surfaceome. Due to high cell number requirements, surface proteomics has been underexploited in AML so far, although surface proteome analysis of AML cell lines and small cohorts of primary human AML specimens paved the way for antigen identification23-25. Herein, we compared global and surface proteomic datasets generated from primary human AML specimens and show that surfaceome analysis uniquely identifies a larger subset of cell surface proteins compared to global proteomics. We therefore built a cohort of 100 primary human AML specimens that was subjected to surface proteome analysis and served as a primary dataset for antigen identification. A significant portion of the cohort also underwent single-cell RNA sequencing, which allowed the exploration of antigen expression at the population level and the selection of AML antigens expressed by primitive blasts. These analyses led to the identification of novel AML antigens expressed by the majority of AML specimens of the cohort, of antigens overexpressed by specific AML subgroups, as well as of previously uncovered potential leukemia stem cell (LSC) markers, and represents the first large-scale surface proteomic study in AML.
2024-05-21 | PXD044480 | Pride
Project description:We exploited the extensive genomic diversity of the Leucegene cohort of primary human AML specimens to provide an overview of the human AML surfaceome. Due to high cell number requirements, surface proteomics has been underexploited in AML so far, although surface proteome analysis of AML cell lines and small cohorts of primary human AML specimens paved the way for antigen identification23-25. Herein, we compared global and surface proteomic datasets generated from primary human AML specimens and show that surfaceome analysis uniquely identifies a larger subset of cell surface proteins compared to global proteomics. We therefore built a cohort of 100 primary human AML specimens that was subjected to surface proteome analysis and served as a primary dataset for antigen identification. A significant portion of the cohort also underwent single-cell RNA sequencing, which allowed the exploration of antigen expression at the population level and the selection of AML antigens expressed by primitive blasts. These analyses led to the identification of novel AML antigens expressed by the majority of AML specimens of the cohort, of antigens overexpressed by specific AML subgroups, as well as of previously uncovered potential leukemia stem cell (LSC) markers, and represents the first large-scale surface proteomic study in AML.
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Project description:Synergistic Targeting of Menin in AML
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Project description:Targeting mitochondrial structure sensitizes AML to Venetoclax
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Project description:Menin inhibitors have demonstrated profound preclinical activity in MLL1-rearranged and NPM1 mutated AML and in this context, ziftomenib is a novel compound currently assessed in a clinical phase I/II trials. We assessed preclinical effects of ziftomenib and demonstrate profound synergy in combination with compounds targeting chromatin regulation and apoptosis including the BCL2 inhibitor venetoclax which was validated in primary AML samples and an MLL-r and NPM1 mutated AML xenograft model.
2023-05-01 | GSE228307 | 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.
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Project description:Although the landscape for treating acute myeloid leukemia (AML) patients has changed substantially in recent years, the majority of patients will eventually relapse and succumb to their disease. Allogeneic stem cell transplantation provides the best anti-leukemia treatment strategy, but is only suitable in a minority of patients. In contrast to B-cell neoplasias, chimeric antigen receptor (CAR) T-cell therapy in AML has encountered challenges in target antigen heterogeneity, safety, and T-cell dysfunction. We developed a Fab-based adapter CAR (AdCAR) T-cell platform with flexibility of targeting and control of AdCAR T-cell activation. Utilizing AML cell lines and a long-term culture assay for primary AML cells, we were able to demonstrate AML-specific cytotoxicity using anti-CD33, anti-CD123, and anti-CLL1 adapter molecules in vitro and in vivo. Notably, we show for the first time the feasibility of sequential application of adapter molecules of different specificity in primary AML co-cultures. Importantly, utilizing the AML platform, we were able to demonstrate that continuous adapter molecule exposure led to AdCAR T-cell exhaustion through chronic AdCAR stimulation, which was counteracted through treatment-free intervals. As CAR T-cell exhaustion is a well-known cause of resistance, the AdCAR platform might ameliorate CAR T-cell dysfunction.
2023-09-08 | GSE221070 | GEO
Project description:Persistent therapy-resistant leukemic progenitor cells (LPC) are a main cause of disease relapse and recurrence in acute myeloid leukemia (AML). Specific LPC-targeting therapies may thus improve treatment outcome of AML patients. We demonstrate that LPCs present human leukocyte antigen (HLA)-restricted cancer antigens that induce T cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach we characterized the antigenic landscape of patient LPCs and identify AML/LPC-associated HLA-presented antigens as well as mutation-derived and cryptic neoepitopes as prime targets for development of T cell-based immunotherapeutic approaches. We observed frequent spontaneous memory T cells targeting these AML/LPC-associated antigens in AML patients and showed that antigen-specific T cell recognition and HLA class II immunopeptidome diversity impacts clinical outcome. Our results pave the way for implementation of AML/LPC-associated antigens for T cell-based immunotherapeutic approaches to specifically target and eliminate residual LPCs in AML patients.
2023-08-23 | PXD038691 | Pride
Project description:<p>We developed a novel microfluidic platform to automatically barcode genomic DNA from individual cancer cells. Using this approach, we sequenced acute myeloid leukemia (AML) tumors targeting up to 62 loci relevant for the disease from thousands of cells. We predict that our platform will enable analysis of heterogeneity in AML and improve stratification and therapy selection.</p>
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