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

Abstract

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.

Immunotherapy targeting mesothelin in acute myeloid leukemia

“…15 Thus, MSLN is a promising target for multiple diseases. 16 These data showed that MSLN is indeed highly expressed in AML but essentially absent in the normal bone marrow. Transcriptome sequencing (RNA sequencing) of MSLN-positive AML and solid tumors shows substantial overlap in the MSLN expression level, which indicates that MSLN profiles in these 2 types of tumors are similar.…”

“…However, MSLN expression was rare or absent in FLT3-ITD-, NPM1-, and CEBPα-mutated AML patients. 16,25 In summary, MSLN is indeed highly expressed in AML patients with specific genotypes, and it is not expressed in hematopoietic cells.…”

“…Transcriptome sequencing (RNA sequencing) of MSLN-positive AML and solid tumors shows substantial overlap in the MSLN expression level, which indicates that MSLN profiles in these 2 types of tumors are similar. 16 Even though MSLN was overexpressed in 36% of AML patients, no genome sequencing data showed any genomic alterations in MSLN that could result in high expression. The experimental results showed that hypomethylation of MSLN promoter occurred in both MSLN-positive AML and solid tumors, which may explain the high level of MSLN expression.…”

“…In approximately 36% of pediatric and adult AML cases, the expression of MSLN shows a similar pattern to popular targets such as CD33 and CD123. 16 These data make MSLN an attractive target for the treatment of AML patients. Based on previous research, many immunologic reagents targeting MSLN have been developed and are now in preclinical and clinical trials for solid tumors.…”

Somatic FOXC1 insertion mutation remodels the immune microenvironment and promotes the progression of childhood acute lymphoblastic leukemia

“…To date, the etiology of leukemia has not been fully clear, and current studies suggest that chemical factors, radiation factors, genetic factors and immune factors play important roles in the pathogenesis of leukemia [ 8 ]. The immune system’s role in the occurrence and development of tumors is highly complex.…”