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Cathepsin G is broadly expressed in acute myeloid leukemia and is an effective immunotherapeutic target

Leukemia volume 31, pages 234–237 (2017)Cite this article

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Immunotherapy is among the novel classes of therapy in development for acute myeloid leukemia (AML) and harnesses the specificity of the immune system to eliminate leukemia cells.1 This approach builds upon the success of allogeneic hematopoietic stem cell transplant (allo-SCT) in AML, which can be curative in up to 50% of patients, but often at the cost of high rates of treatment-related toxicities, including graft-versus-host disease (GVHD).2 To avoid this complication, one approach is to refine the potent graft-versus-leukemia effect to target discrete leukemia antigens in the form of adoptive cellular therapy (ACT). Importantly, in order to overcome intratumoral heterogeneity, durable clinical efficacy will likely require targeting multiple leukemia antigens simultaneously, an approach that is currently limited by the number of known effective leukemia antigens.3

We previously reported that cathepsin G (CG), an azurophil granule protease, represents a novel leukemia-associated antigen (LAA).4 CG is largely restricted to the myeloid lineage and, like proteinase 3 (P3) and neutrophil elastase (NE), the sources of the well-established human leukocyte antigen (HLA)-A*0201 (denoted here as HLA-A2) LAA PR1,5 CG is contained within the primary granules of maturing and mature neutrophils. However, CG is expressed later in myeloid differentiation, resides under a different promoter than NE and P3, and demonstrates a distinct pattern of expression, suggesting that targeting both PR1 and CG could be synergistic.6 In our prior work,4 we demonstrated that CG is highly expressed in primary patient AML blasts, AML cell lines and, critically, in leukemia stem cells (LSCs). We showed that CG is localized outside azurophil granules and is ubiquitinated, favoring antigen presentation. In addition, we identified an HLA-A2-restricted epitope within the leader sequence of CG, designated as CG1 (amino-acid sequence FLLPTGAEA) and showed that targeting CG1 resulted in lysis of AML blasts in vitro. Finally, we detected cytotoxic T lymphocytes (CTLs) specific for CG1 in the peripheral blood of AML patients after allo-SCT.4

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Acknowledgements

This work is supported by grants from the Leukemia Research Foundation (GA), National Institutes of Health National Cancer Institute (P50CA100632) (GA) and Leukemia & Lymphoma Society (GA and SK).

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Author notes

  1. H R Garber and M Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, Section of Transplant Immunology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    G Alatrash, H R Garber, M Zhang, P Sukhumalchandra, H Jakher, A A Perakis, L Becker, K C Dwyer, L S St John, A Sergeeva, H He, Q Ma & J J Molldrem

  2. Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA

    Y Qiu & S M Kornblau

  3. Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA

    S Y Yoo

  4. Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA

    K Coombes

  5. Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    A H Talukder, J Roszik & G Lizee

  6. Department of Pediatrics, MD Anderson Cancer Center, Houston, TX, USA

    V Senyukov & D A Lee

  7. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    P M Armistead

  8. Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA

    J Roszik

  9. Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    E A Mittendorf

  10. Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA

    D Hawke

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  1. G Alatrash
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Correspondence to G Alatrash.

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Alatrash, G., Garber, H., Zhang, M. et al. Cathepsin G is broadly expressed in acute myeloid leukemia and is an effective immunotherapeutic target. Leukemia 31, 234–237 (2017). https://doi.org/10.1038/leu.2016.249

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