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.
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.
Haematologica. 2022 Apr 1;107(4):803-815. doi: 10.3324/haematol.2020.257451.
Although great advances have been made in understanding the pathobiology of mixed lineage leukemia-rearranged (MLL-r) leukemias, therapies for this leukemia have remained limited, and clinical outcomes remain bleak. In order 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 innate-immune pathways in MLL-r leukemias. Downregulation of LAMP5 led to inhibition of NF-kB 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 endosomes. 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 in 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.
尽管在理解混合谱系白血病重排（MLL-r）白血病的病理生物学方面已经取得了重大进展，但针对这种白血病的治疗方法仍然有限，临床结果仍然不容乐观。为了确定免疫治疗新靶点，我们使用公开可用的数据集编制了一个谱系独立的 MLL-r 白血病基因特征。通过计算机模拟的人类表面组，对来自大型白血病存储库的数据进行过滤，提供了一个在 MLL-r 白血病中高度预测的细胞表面蛋白列表。溶酶体相关膜蛋白 5（LAMP5）在 MLL-r 白血病中高度特异性表达。我们发现 LAMP5 是致癌性 MLL 融合蛋白的直接靶点。LAMP5 耗竭显著抑制白血病细胞的体外和体内生长。功能研究表明，LAMP-5 是 MLL-r 白血病中先天免疫途径的新型调节剂。下调 LAMP5 导致 NF-kB 信号抑制和 Toll 样受体/白细胞介素 1 受体激活下游的 1 型干扰素信号激活增加。这些效应归因于 LAMP-5 在将信号通量从干扰素信号内体转移到促炎信号内体中的关键作用。IRF7 的耗竭能够部分挽救 LAMP5 下调时的细胞生长抑制。最后，LAMP-5 很容易在 MLL-r 白血病细胞表面检测到。使用抗体药物偶联物靶向表面 LAMP-5 可特异性降低 MLL-r 白血病细胞的活力。总体而言，基于在人体组织中的有限表达，我们推测 LAMP-5 可能作为一种免疫治疗靶点，具有广泛的治疗窗口，可用于治疗 MLL-r 白血病。
