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Gracia-Maldonado G, Clark J, Burwinkel M, et al. LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for Mixed Lineage Leukemia-Rearranged acute leukemia. Haematologica. 2021;doi: 10.3324/haematol.2020.257451.
Gracia-Maldonado, G., Clark, J., Burwinkel, M., Greenslade, B., Wunderlich, M., Salomonis, N., Leone, D., Gatti, E., Pierre, P., Kumar, A. R., & Lee, L. H. (2021). LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for Mixed Lineage Leukemia-Rearranged acute leukemia. Haematologica, . https://doi.org/10.3324/haematol.2020.257451
Gracia-Maldonado, Gabriel, et al. "LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for Mixed Lineage Leukemia-Rearranged acute leukemia." Haematologica vol. (2021). doi: https://doi.org/10.3324/haematol.2020.257451
Gracia-Maldonado G, Clark J, Burwinkel M, Greenslade B, Wunderlich M, Salomonis N, Leone D, Gatti E, Pierre P, Kumar AR, Lee LH. LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for Mixed Lineage Leukemia-Rearranged acute leukemia. Haematologica. 2021 Apr 29; doi: 10.3324/haematol.2020.257451. Epub 2021 Apr 29. PMID: 33910331.
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Haematologica. 2021 Apr 29; doi: 10.3324/haematol.2020.257451. Epub 2021 Apr 29.

LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for Mixed Lineage Leukemia-Rearranged acute leukemia.

Haematologica

Gabriel Gracia-Maldonado, Jason Clark, Matthew Burwinkel, Brenay Greenslade, Mark Wunderlich, Nathan Salomonis, Dario Leone, Evelina Gatti, Philippe Pierre, Ashish R Kumar, Lynn H Lee

Affiliations

  1. Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati, Children's Hospital Medical Center, Cincinnati, OH, 45229.
  2. Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229.
  3. Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Division of Experimental Hematology and Cancer Biology, Cincinnati, Children's Hospital Medical Center, Cincinnati, OH, 45229.
  4. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229.
  5. Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), 13288 Marseille Cedex 9.
  6. Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati, Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, 45229. [email protected].
  7. Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, 45229. [email protected].

PMID: 33910331 DOI: 10.3324/haematol.2020.257451

Abstract

Although great advances have been made in understanding the pathobiology of MLL-rearranged (MLL-r) leukemias, therapies for this leukemia have remained limited, and clinical outcomes remain bleak. To identify novel targets for immunotherapy treatments, we compiled a lineage-independent MLL-r leukemia gene signature using publicly available data sets. Data from large leukemia repositories were filtered through the In-silico Human Surfaceome, providing a list of highly predicted cell surface proteins overexpressed in MLL-r leukemias. LAMP5, a lysosomal associated membrane protein, is expressed highly and specifically in MLL-r leukemia. We found that LAMP5 is a direct target of the oncogenic MLL-fusion protein. LAMP5 depletion significantly inhibited leukemia cell growth in vitro and in vivo. Functional studies showed that LAMP-5 is a novel modulator of innateimmune pathways in MLL-r leukemias. Downregulation of LAMP5 led to inhibition of NF-κB signaling and increased activation of type-1 interferon signaling downstream of Toll-like Receptor/Interleukin 1 Receptor activation. These effects were attributable to the critical role of LAMP-5 in transferring the signal flux from Interferon Signaling Endosomes to Pro-Inflammatory Signaling Endosome. Depletion of IRF7 was able to partially rescue the cell growth inhibition upon LAMP5 downregulation. Lastly, LAMP-5 was readily detected on the surface of MLL-r leukemia cells. Targeting surface LAMP-5 using an antibody-drug conjugate leads to significant cell viability decrease specifically on MLL-r leukemias. Overall, based on the limited expression throughout human tissues, we postulate that LAMP-5 could potentially serve as an immunotherapeutic target with a wide therapeutic window to treat MLL-r leukemias.

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