Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Acute Myeloid Malignancies, AML, Biological therapies, Antibody Therapy, adult, bioinformatics, Diseases, Myeloid Malignancies, Technology and Procedures, Study Population, Human, omics technologies
METHODS AND RESULTS. We used a proteomics-based approach to analyze the surfaceome of 100 primary human AML specimens from 13 different AML subgroups, including 13 KMT2Ar AML samples. Briefly, we combined cell surface biotinylation with streptavidin affinity purification to enrich cell extracts with cell surface proteins, which were then analyzed by LC-MS/MS to obtain an overview of primary AML sample surfaceomes. Differential surfaceome analyses were performed to identify surface proteins selectively expressed by KMT2Ar AML specimens, and proteins with low expression in normal hematopoietic cells and normal tissues, as determined by expression analyses using publicly available datasets, were further selected. Using this approach, we identified several potential KMT2Ar AML surface antigens, including CD93, reported to be expressed by KMT2Ar AML stem cells. We then analyzed surface expression of these antigens by flow cytometry using a collection of 112 primary human AML specimens including 10 KMT2Ar AML samples. Results indicate that in the majority of KMT2Ar AML samples analyzed, more than 90% of blasts express selected antigens, suggesting that targeting these antigens with immunotherapeutic approaches could potentially lead to the elimination of most AML cells. Furthermore, flow cytometry data showed specificity of antigen expression for KMT2Ar AML samples, opening new therapeutic opportunities for this AML subgroup. Finally, single cell RNA sequencing of 8 primary KMT2Ar AML specimens was performed to further analyze the expression profile of these antigens in patient samples. AML specimens harboring the MLLT3::KMT2A fusion expressed these antigens in the vast majority of blast cells, confirming the homogeneous expression profile of identified antigens and the high interest to target these antigens for KMT2Ar AML.
CONCLUSIONS Using a cell surface proteomics-based approach for the analysis of KMT2Ar AML surfaceome, we identified several antigens for this AML subgroup with high therapeutic potential. These antigens are very specific for KMT2Ar AML and are expressed homogeneously in primary human KMT2Ar AML samples, suggesting that targeting these antigens represents a promising therapeutic strategy for these patients. Several immunotherapeutic approaches to target these antigens are currently being developed and tested by our group, with the hope of identifying novel therapeutic strategies for the treatment of KMT2Ar AML.
Disclosures: Lavallée: BMS: Research Funding. Hebert: BMS: Research Funding. Sauvageau: BMS: Research Funding; ExCellThera: Consultancy, Current Employment, Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Roux: BMS: Research Funding.
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