Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups
Abstract Background Immunotherapy is now standard of care for multiple myeloma (MM), where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D (GPRC5D). However, additional novel targets are needed to counter tumor heterogeneity, there...
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| Format: | Article |
| Language: | English |
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BMC
2025-07-01
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| Series: | Genome Medicine |
| Online Access: | https://doi.org/10.1186/s13073-025-01503-y |
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| author | Enze Liu Oumaima Jaouadi Riya Sharma Nathan Becker Travis S. Johnson Parvathi Sudha Vivek S. Chopra Faiza Zafar Habib Hamidi Charlotte Pawlyn Attaya Suvannasankha Rafat Abonour Brian A. Walker |
| author_facet | Enze Liu Oumaima Jaouadi Riya Sharma Nathan Becker Travis S. Johnson Parvathi Sudha Vivek S. Chopra Faiza Zafar Habib Hamidi Charlotte Pawlyn Attaya Suvannasankha Rafat Abonour Brian A. Walker |
| author_sort | Enze Liu |
| collection | DOAJ |
| description | Abstract Background Immunotherapy is now standard of care for multiple myeloma (MM), where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D (GPRC5D). However, additional novel targets are needed to counter tumor heterogeneity, therefore new strategies to identify additional targets are also required. Methods We utilized multi-omics data from two large datasets A framework that utilized prior knowledge of cell surface potential, expression in healthy organs, and expression level in MM cells was established to define novel immunotherapeutic targets. High confidence targets were prioritized for myeloma populations and subgroups, validated with flow cytometry and immunoblotting. Results Novel population-level candidate targets such as ITGA4 and LAX1, as well as subtype-specific targets including ROBO3 in t(4;14), CD109 in t(14;16), CD20 in t(11;14), CD180 in hyperdiploidy, GPRC5D in 1q gain, and ADAM28 in biallelic TP53 samples were identified. Candidate target surface expression was validated by flow cytometry and CRISPR-Cas9 knock-out models. Sub-clonal differences in expression were noted, using single-cell RNA-seq data. Additionally, alternative splicing of existing immunotherapy targets, such as FCRL5, was noted as a potential mechanism of antigen loss. Conclusions Our study presents a methodology to identify novel candidate immunotherapy targets. We also use known genomic data to identify subtype-specific targets that could be used either as complementary or alternative targets to existing treatments. We show that immunotherapy targets can have heterogenous expression within a patient, which can affect treatment efficacy. Taken together, our study establishes a robust methodology to identify novel therapeutic targets in MM, revealing critical insights that will inform the development of current and next-generation immunotherapies. |
| format | Article |
| id | doaj-art-c9fa2b0a1ae24b249520e9b68a20a812 |
| institution | Kabale University |
| issn | 1756-994X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj-art-c9fa2b0a1ae24b249520e9b68a20a8122025-08-20T03:46:28ZengBMCGenome Medicine1756-994X2025-07-0117111810.1186/s13073-025-01503-yUtilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroupsEnze Liu0Oumaima Jaouadi1Riya Sharma2Nathan Becker3Travis S. Johnson4Parvathi Sudha5Vivek S. Chopra6Faiza Zafar7Habib Hamidi8Charlotte Pawlyn9Attaya Suvannasankha10Rafat Abonour11Brian A. Walker12Melvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana UniversityMelvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana UniversityMelvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana UniversityMyeloma Institute, Sylvester Comprehensive Cancer Center, University of MiamiDepartment of Biostatistics and Health Data Sciences, School of Medicine, Indiana UniversityMelvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana UniversityGenentech IncGenentech IncGenentech IncInstitute of Cancer ResearchMelvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana UniversityMelvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana UniversityMelvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana UniversityAbstract Background Immunotherapy is now standard of care for multiple myeloma (MM), where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D (GPRC5D). However, additional novel targets are needed to counter tumor heterogeneity, therefore new strategies to identify additional targets are also required. Methods We utilized multi-omics data from two large datasets A framework that utilized prior knowledge of cell surface potential, expression in healthy organs, and expression level in MM cells was established to define novel immunotherapeutic targets. High confidence targets were prioritized for myeloma populations and subgroups, validated with flow cytometry and immunoblotting. Results Novel population-level candidate targets such as ITGA4 and LAX1, as well as subtype-specific targets including ROBO3 in t(4;14), CD109 in t(14;16), CD20 in t(11;14), CD180 in hyperdiploidy, GPRC5D in 1q gain, and ADAM28 in biallelic TP53 samples were identified. Candidate target surface expression was validated by flow cytometry and CRISPR-Cas9 knock-out models. Sub-clonal differences in expression were noted, using single-cell RNA-seq data. Additionally, alternative splicing of existing immunotherapy targets, such as FCRL5, was noted as a potential mechanism of antigen loss. Conclusions Our study presents a methodology to identify novel candidate immunotherapy targets. We also use known genomic data to identify subtype-specific targets that could be used either as complementary or alternative targets to existing treatments. We show that immunotherapy targets can have heterogenous expression within a patient, which can affect treatment efficacy. Taken together, our study establishes a robust methodology to identify novel therapeutic targets in MM, revealing critical insights that will inform the development of current and next-generation immunotherapies.https://doi.org/10.1186/s13073-025-01503-y |
| spellingShingle | Enze Liu Oumaima Jaouadi Riya Sharma Nathan Becker Travis S. Johnson Parvathi Sudha Vivek S. Chopra Faiza Zafar Habib Hamidi Charlotte Pawlyn Attaya Suvannasankha Rafat Abonour Brian A. Walker Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups Genome Medicine |
| title | Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups |
| title_full | Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups |
| title_fullStr | Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups |
| title_full_unstemmed | Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups |
| title_short | Utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high-risk subgroups |
| title_sort | utilizing genomics to identify novel immunotherapeutic targets in multiple myeloma high risk subgroups |
| url | https://doi.org/10.1186/s13073-025-01503-y |
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