LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia.
LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia.
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DOI：
10.3324/haematol.2020.257451
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发表时间：
2022-04-01
期刊：
影响因子：
10.1
通讯作者：
Lee LH
中科院分区：
文献类型：
--
作者：
Gracia-Maldonado G;Clark J;Burwinkel M;Greenslade B;Wunderlich M;Salomonis N;Leone D;Gatti E;Pierre P;Kumar AR;Lee LH
尽管对混合血统白血病-重排(MLL-r)白血病的病理生物学研究取得了很大进展，但对这种白血病的治疗仍然有限，临床结果仍然黯淡。为了确定免疫治疗的新靶点，我们使用公开可用的数据集编制了一个不依赖于谱系的MLL-r白血病基因签名。来自大型白血病资料库的数据通过电子人类表面组进行筛选，提供了一份高度预测的在MLL-r白血病中过度表达的细胞表面蛋白的清单。LAMP5是一种溶酶体相关膜蛋白，在MLL-r白血病中高表达且具有特异性。我们发现LAMP5是癌基因MLL融合蛋白的直接靶点。LAMP5缺失可显著抑制白血病细胞的体内外生长。功能研究表明，LAMP-5是MLL-r白血病天然免疫通路的一种新的调节剂。在Toll样受体/白介素1受体激活的下游，LAMP5的下调导致核因子-kB信号的抑制和1型干扰素信号的激活。这些效应归因于LAMP-5在将干扰素信号内体的信号流转移到促炎信号内体中的关键作用。去除IRF7可以部分挽救LAMP5下调对细胞生长的抑制作用。MLL-r白血病细胞表面容易检测到LAMP-5。使用抗体-药物结合物靶向表面LAMP-5会导致细胞存活率显著降低，特别是在MLL-r白血病中。总体而言，基于在整个人类组织中有限的表达，我们推测LAMP-5可能作为免疫治疗的靶点，具有广泛的治疗窗口来治疗MLL-r白血病。
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.
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DOI：
10.1073/pnas.1808790115
发表时间：
2018-11-13
影响因子：
11.1
作者：
Bausch-Fluck D;Goldmann U;Müller S;van Oostrum M;Müller M;Schubert OT;Wollscheid B
通讯作者：
Wollscheid B
影响因子：
16.6
作者：
Jacoby E;Nguyen SM;Fountaine TJ;Welp K;Gryder B;Qin H;Yang Y;Chien CD;Seif AE;Lei H;Song YK;Khan J;Lee DW;Mackall CL;Gardner RA;Jensen MC;Shern JF;Fry TJ
通讯作者：
Fry TJ
影响因子：
11.4
作者：
Godfrey L;Crump NT;O'Byrne S;Lau IJ;Rice S;Harman JR;Jackson T;Elliott N;Buck G;Connor C;Thorne R;Knapp DJHF;Heidenreich O;Vyas P;Menendez P;Inglott S;Ancliff P;Geng H;Roberts I;Roy A;Milne TA
通讯作者：
Milne TA
影响因子：
20.3
作者：
Faber, Joerg;Krivtsov, Andrei V.;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
影响因子：
8.8
作者：
Benito JM;Godfrey L;Kojima K;Hogdal L;Wunderlich M;Geng H;Marzo I;Harutyunyan KG;Golfman L;North P;Kerry J;Ballabio E;Chonghaile TN;Gonzalo O;Qiu Y;Jeremias I;Debose L;O'Brien E;Ma H;Zhou P;Jacamo R;Park E;Coombes KR;Zhang N;Thomas DA;O'Brien S;Kantarjian HM;Leverson JD;Kornblau SM;Andreeff M;Müschen M;Zweidler-McKay PA;Mulloy JC;Letai A;Milne TA;Konopleva M
通讯作者：
Konopleva M