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

Gabriel Gracia-Maldonado (1) , Jason Clark (1) , Matthew Burwinkel (1) , Brenay Greenslade (1) , Mark Wunderlich (1) , Nathan Salomonis (1) , Dario Leone (2) , Evelina Gatti (2) , Philippe Pierre (2) , Ashish Kumar (1) , Lynn Lee (1)

1 Cincinnati Children's Hospital Medical Center
2 CIML - Centre d'Immunologie de Marseille - Luminy

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.

Domaines: Sciences du Vivant [q-bio]

Gabriel Gracia-Maldonado, Jason Clark, Matthew Burwinkel, Brenay Greenslade, Mark Wunderlich, et al.. LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for Mixed Lineage Leukemia-Rearranged acute leukemia. Haematologica, 2020, ⟨10.3324/haematol.2020.257451⟩. ⟨hal-03385563⟩