Mesothelin is a novel cell surface disease marker and potential therapeutic target in acute myeloid leukemia
| Autor: | Anilkumar Gopalakrishnapillai, Todd A. Alonzo, Soheil Meshinchi, Min Xu, Steven M. Kornblau, Lisa Broderson, E. Anders Kolb, Timothy J. Triche, Jenny L. Smith, Sonali P. Barwe, Quy Le, Michael R. Loken, Amanda R. Leonti, Colin Correnti, Laura Pardo, Cassie K. Chou, Robert B. Gerbing, Allison Kaeding, Rhonda E. Ries, Katherine Tarlock, Thao T. Tang |
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| Rok vydání: | 2021 |
| Předmět: |
Myeloid
GPI-Linked Proteins Flow cytometry Young Adult In vivo hemic and lymphatic diseases medicine Humans Mesothelin Child Myeloid Neoplasia medicine.diagnostic_test biology business.industry Myeloid leukemia Hematology medicine.disease Reverse transcription polymerase chain reaction Leukemia Myeloid Acute Leukemia KMT2A medicine.anatomical_structure biology.protein Cancer research business |
| Zdroj: | Blood Adv |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | In an effort to identify acute myeloid leukemia (AML)-restricted targets for therapeutic development in AML, we analyzed the transcriptomes of 2051 children and young adults with AML and compared the expression profile with normal marrow specimens. This analysis identified a large cohort of AML-restricted genes with high expression in AML, but low to no expression in normal hematopoiesis. Mesothelin (MSLN), a known therapeutic target in solid tumors, was shown to be highly overexpressed in 36% of the AML cohort (range, 5-1077.6 transcripts per million [TPM]) and virtually absent in normal marrow (range, 0.1-10.7 TPM). We verified MSLN transcript expression by quantitative reverse transcription polymerase chain reaction, confirmed cell surface protein expression on leukemic blasts by multidimensional flow cytometry, and demonstrated that MSLN expression was associated with promoter hypomethylation. MSLN was highly expressed in patients with KMT2A rearrangements (P < .001), core-binding factor fusions [inv(16)/t(16;16), P < .001; t(8;21), P < .001], and extramedullary disease (P = .001). We also demonstrated the presence of soluble MSLN in diagnostic serum specimens using an MSLN-directed enzyme-linked immunosorbent assay. In vitro and in vivo preclinical efficacy of the MSLN-directed antibody-drug conjugates (ADCs) anetumab ravtansine and anti-MSLN–DGN462 were evaluated in MSLN+ leukemia cell lines in vitro and in vivo, as well as in patient-derived xenografts. Treatment with ADCs resulted in potent target-dependent cytotoxicity in MSLN+ AML. In this study, we demonstrate that MSLN is expressed in a significant proportion of patients with AML and holds significant promise as a diagnostic and therapeutic target in AML, and that MSLN-directed therapeutic strategies, including ADCs, warrant further clinical investigation. |
| Databáze: | OpenAIRE |
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