TY - JOUR
T1 - Mesothelin is a novel cell surface disease marker and potential therapeutic target in acute myeloid leukemia
AU - Kaeding, Allison J.
AU - Barwe, Sonali P.
AU - Gopalakrishnapillai, Anilkumar
AU - Ries, Rhonda E.
AU - Alonzo, Todd A.
AU - Gerbing, Robert B.
AU - Correnti, Colin
AU - Loken, Michael R.
AU - Broderson, Lisa Eidenschink
AU - Pardo, Laura
AU - Le, Quy H.
AU - Tang, Thao
AU - Leonti, Amanda R.
AU - Smith, Jenny L.
AU - Chou, Cassie K.
AU - Xu, Min
AU - Triche, Tim
AU - Kornblau, Steven M.
AU - Kolb, E. Anders
AU - Tarlock, Katherine
AU - Meshinchi, Soheil
N1 - Funding Information:
This work was supported by the St. Baldrick’s Foundation, a St. Baldrick’s Scholar Award (K.T.), a St. Baldrick’s Consortium Grant (S.M.), TARGET Pediatric AML (S.M.), the Leukemia and Lymphoma Society (6558-18 [S.M. and E.A.K] and 6604-20 [S.M.]), National Institutes of Health, National Cancer Institute Research Training and Career Development grants K12-CA076930 (A.J.K.) and T32-CA009351 (A.J.K.), and Research Grant Program R01-CA114563-10 (S.M.), Department of Health and Human Services HHSN-261200800001E (S.M.), the Andrew McDonough B+ Foundation (S.M.), the American Society of Clinical Oncology Conquer Cancer Foundation (A.J.K.), a COG Chair’s grant (U10-CA098543) (S.M.), the Children’s Oncology Group Foundation (K.T.), Hyundai Hope on Wheels (S.M.), the National Cancer Institute’s National Clinical Trials Network Statistics and Data Center (U10-CA180899) (S.M. and T.A.A.), Project Stella (S.M.), the Rally Foundation/Truth 365 (A.J.K.), and Leukemia Research Foundation of Delaware (S.P.B. and A.G.). This study used the computational infrastructure of FHCRC Scientific Computing, which is funded by the Office of Research Infrastructure Programs grant S10OD028685.
Publisher Copyright:
© 2021 by The American Society of Hematology
PY - 2021/5/3
Y1 - 2021/5/3
N2 - 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.
AB - 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.
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U2 - 10.1182/BLOODADVANCES.2021004424
DO - 10.1182/BLOODADVANCES.2021004424
M3 - Article
C2 - 33938941
AN - SCOPUS:85106356165
SN - 2473-9529
VL - 5
SP - 2350
EP - 2361
JO - Blood Advances
JF - Blood Advances
IS - 9
ER -