Mesothelin is a novel cell surface disease marker and potential therapeutic target in acute myeloid leukemia

Allison J. Kaeding, Sonali P. Barwe, Anilkumar Gopalakrishnapillai, Rhonda E. Ries, Todd A. Alonzo, Robert B. Gerbing, Colin Correnti, Michael R. Loken, Lisa Eidenschink Broderson, Laura Pardo, Quy H. Le, Thao Tang, Amanda R. Leonti, Jenny L. Smith, Cassie K. Chou, Min Xu, Tim Triche, Steven M. Kornblau, E. Anders Kolb, Katherine TarlockSoheil Meshinchi

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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 5.001). 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 MSLN1 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 MSLN1 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.

Original languageEnglish
Pages (from-to)2350-2361
Number of pages12
JournalBlood advances
Issue number9
StatePublished - 3 May 2021
Externally publishedYes


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