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1.
Leukemia ; 38(5): 1019-1031, 2024 May.
Article in English | MEDLINE | ID: mdl-38627586

ABSTRACT

The hypomethylating agent 5-azacytidine (AZA) is the first-line treatment for AML patients unfit for intensive chemotherapy. The effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, evidence supporting higher ERE MAPs presentation after AZA treatment is lacking. Therefore, using proteogenomics, we examined the impact of AZA on the repertoire of MAPs and their source transcripts. AZA-treated AML upregulated both CTA and ERE transcripts, but only CTA MAPs were presented at greater levels. Upregulated ERE transcripts triggered innate immune responses against double-stranded RNAs but were degraded by autophagy, and not processed into MAPs. Autophagy resulted from the formation of protein aggregates caused by AZA-dependent inhibition of DNMT2. Autophagy inhibition had an additive effect with AZA on AML cell proliferation and survival, increased ERE levels, increased pro-inflammatory responses, and generated immunogenic tumor-specific ERE-derived MAPs. Finally, autophagy was associated with a lower abundance of CD8+ T-cell markers in AML patients expressing high levels of EREs. This work demonstrates that AZA-induced EREs are degraded by autophagy and shows that inhibiting autophagy can improve the immune recognition of AML blasts in treated patients.


Subject(s)
Antimetabolites, Antineoplastic , Autophagy , Azacitidine , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/pathology , Azacitidine/pharmacology , Autophagy/drug effects , Antimetabolites, Antineoplastic/pharmacology , Antimetabolites, Antineoplastic/therapeutic use , DNA Methylation/drug effects , Cell Proliferation , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology
2.
Cell Rep ; 40(7): 111241, 2022 08 16.
Article in English | MEDLINE | ID: mdl-35977509

ABSTRACT

Previous reports showed that mouse vaccination with pluripotent stem cells (PSCs) induces durable anti-tumor immune responses via T cell recognition of some elusive oncofetal epitopes. We characterize the MHC I-associated peptide (MAP) repertoire of human induced PSCs (iPSCs) using proteogenomics. Our analyses reveal a set of 46 pluripotency-associated MAPs (paMAPs) absent from the transcriptome of normal tissues and adult stem cells but expressed in PSCs and multiple adult cancers. These paMAPs derive from coding and allegedly non-coding (48%) transcripts involved in pluripotency maintenance, and their expression in The Cancer Genome Atlas samples correlates with source gene hypomethylation and genomic aberrations common across cancer types. We find that several of these paMAPs were immunogenic. However, paMAP expression in tumors coincides with activation of pathways instrumental in immune evasion (WNT, TGF-ß, and CDK4/6). We propose that currently available inhibitors of these pathways could synergize with immune targeting of paMAPs for the treatment of poorly differentiated cancers.


Subject(s)
Induced Pluripotent Stem Cells , Neoplasms , Pluripotent Stem Cells , Animals , Histocompatibility Antigens Class I/metabolism , Humans , Mice , Neoplasms/metabolism , Peptides/metabolism , Pluripotent Stem Cells/metabolism
3.
Blood Adv ; 6(2): 509-514, 2022 01 25.
Article in English | MEDLINE | ID: mdl-34731885

ABSTRACT

Cholesterol homeostasis has been proposed as one mechanism contributing to chemoresistance in AML and hence, inclusion of statins in therapeutic regimens as part of clinical trials in AML has shown encouraging results. Chemical screening of primary human AML specimens by our group led to the identification of lipophilic statins as potent inhibitors of AMLs from a wide range of cytogenetic groups. Genetic screening to identify modulators of the statin response uncovered the role of protein geranylgeranylation and of RAB proteins, coordinating various aspect of vesicular trafficking, in mediating the effects of statins on AML cell viability. We further show that statins can inhibit vesicle-mediated transport in primary human specimens, and that statins sensitive samples show expression signatures reminiscent of enhanced vesicular trafficking. Overall, this study sheds light into the mechanism of action of statins in AML and identifies a novel vulnerability for cytogenetically diverse AML.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Leukemia, Myeloid, Acute , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics
4.
Immunity ; 54(4): 737-752.e10, 2021 04 13.
Article in English | MEDLINE | ID: mdl-33740418

ABSTRACT

Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy.


Subject(s)
Epitopes/genetics , Histocompatibility Antigens Class I/genetics , Leukemia, Myeloid, Acute/genetics , Animals , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Cell Line , Epigenesis, Genetic/genetics , Epigenesis, Genetic/immunology , Epitopes/immunology , Histocompatibility Antigens Class I/immunology , Humans , Immunotherapy/methods , Leukemia, Myeloid, Acute/immunology , Mice , Mice, Inbred NOD , Mice, SCID , Mutation/genetics , Mutation/immunology , Neoplastic Stem Cells/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes, Cytotoxic/immunology
5.
Int J Cancer ; 147(7): 2000-2006, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32163592

ABSTRACT

The THP-1 cell line is broadly used as a model for acute myeloid leukemia (AML) with MLL fusion and to study monocyte differentiation and function. We studied THP-1 cells obtained from two major biorepositories. The two cell lines were closely related with a percentage match of short tandem repeat (STR) profiles ranging from 93.75% to 100%, depending on the algorithm used. Nevertheless, we found that the two cell lines presented discordant HLA type, cytogenetic aberrations and AML-related gene expression (including critical targets of MLL fusion). These discrepancies resulted mainly from loss of heterozygosity (LOH) involving five chromosomal regions. In view of their aberrant expression of key "leukemia" genes (e.g., LIN28B, MEIS1 and SPARC), we argue that one of the THP-1 cell lines may not be a reliable model for studying leukemia. Their defective expression of HLA molecules and abnormal adhesion properties is also a caveat for studies of antigen presentation. In a more general perspective, our findings show that seemingly minor discrepancies in STR profiles among cell lines may be the sign of major genetic drift, of sufficient magnitude to affect the reliability of cell line-based research.


Subject(s)
Histone-Lysine N-Methyltransferase/genetics , Microsatellite Repeats , Myeloid-Lymphoid Leukemia Protein/genetics , THP-1 Cells/cytology , Algorithms , Biological Specimen Banks , Cell Adhesion , Cytogenetic Analysis , Gene Expression Profiling , Histocompatibility Testing , Humans , Loss of Heterozygosity , Models, Biological , Oncogene Proteins, Fusion/genetics , Reproducibility of Results , Sequence Analysis, RNA , THP-1 Cells/metabolism
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