Jimbo Koji, Hattori Ayuna, Koide Shuhei, Ito Takahiro, Sasaki Katsuhiro, Iwai Kazuhiro, Nannya Yasuhito, Iwama Atsushi, Tojo Arinobu, Konuma Takaaki
Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Division of Stem Cell and Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Leukemia. 2023 Jan;37(1):122-133. doi: 10.1038/s41375-022-01750-7. Epub 2022 Nov 9.
We investigated the role of Hoip, a catalytic subunit of linear ubiquitin chain assembly complex (LUBAC), in adult hematopoiesis and myeloid leukemia by using both conditional deletion of Hoip and small-molecule chemical inhibitors of Hoip. Conditional deletion of Hoip led to significantly longer survival and marked depletion of leukemia burden in murine myeloid leukemia models. Nevertheless, a competitive transplantation assay showed the reduction of donor-derived cells in the bone marrow of recipient mice was relatively mild after conditional deletion of Hoip. Although both Hoip-deficient hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) impaired the maintenance of quiescence, conditional deletion of Hoipinduced apoptosis in LSCs but not HSCs in vivo. Structure-function analysis revealed that LUBAC ligase activity and the interaction of LUBAC subunits were critical for the propagation of leukemia. Hoip regulated oxidative phosphorylation pathway independently of nuclear factor kappa B pathway in leukemia, but not in normal hematopoietic cells. Finally, the administration of thiolutin, which inhibits the catalytic activity of Hoip, improved the survival of recipients in murine myeloid leukemia and suppressed propagation in the patient-derived xenograft model of myeloid leukemia. Collectively, these data indicate that inhibition of LUBAC activity may be a valid therapeutic target for myeloid leukemia.
我们通过条件性敲除Hoip以及使用Hoip的小分子化学抑制剂，研究了线性泛素链组装复合物（LUBAC）的催化亚基Hoip在成体造血和髓系白血病中的作用。在小鼠髓系白血病模型中，条件性敲除Hoip导致生存期显著延长，白血病负担明显减轻。然而，竞争性移植试验表明，条件性敲除Hoip后，受体小鼠骨髓中供体来源细胞的减少相对较轻。尽管Hoip缺陷的造血干细胞（HSC）和白血病干细胞（LSC）均损害了静止状态的维持，但在体内，条件性敲除Hoip可诱导LSC凋亡，而不诱导HSC凋亡。结构-功能分析表明，LUBAC连接酶活性和LUBAC亚基的相互作用对白血病的进展至关重要。在白血病中，Hoip独立于核因子κB途径调节氧化磷酸化途径，但在正常造血细胞中则不然。最后，给予抑制Hoip催化活性的硫藤黄菌素可提高小鼠髓系白血病受体的生存率，并抑制髓系白血病患者来源异种移植模型中的肿瘤进展。总体而言，这些数据表明抑制LUBAC活性可能是髓系白血病的一个有效的治疗靶点。
