Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia
Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia
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DOI：
10.1038/s41375-022-01750-7
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发表时间：
2022-11
期刊：
影响因子：
11.4
通讯作者：
Koji Jimbo;Ayuna Hattori;S. Koide;Takahiro Ito;Katsuhiro Sasaki;K. Iwai;Y. Nannya;A. Iwama;A. Tojo;T. Konuma
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作者：
Koji Jimbo;Ayuna Hattori;S. Koide;Takahiro Ito;Katsuhiro Sasaki;K. Iwai;Y. Nannya;A. Iwama;A. Tojo;T. Konuma
我们研究了Hoip，线性泛素链组装复合物（LUBAC）的催化亚基，在成人造血和髓系白血病中的作用，通过使用条件性删除Hoip和小分子化学抑制剂Hoip。在小鼠髓性白血病模型中，Hoip的条件性缺失导致显著更长的存活期和白血病负荷的显著消耗。然而，竞争性移植试验表明，在条件性删除Hoip后，受体小鼠骨髓中供体来源的细胞的减少相对温和。尽管Hoip缺陷的造血干细胞（HSC）和白血病干细胞（LSC）都损害了静止状态的维持，但Hoip的条件性缺失在体内诱导LSC而不是HSC的凋亡。结构-功能分析表明，LUBAC连接酶活性和LUBAC亚基之间的相互作用是白血病增殖的关键。Hoip在白血病中独立于核因子κ B途径调节氧化磷酸化途径，而在正常造血细胞中不起作用。最后，给药抑制Hoip的催化活性的硫代巴比妥改善了小鼠髓性白血病中受体的存活率，并抑制了髓性白血病患者来源的异种移植模型中的增殖。总的来说，这些数据表明，抑制LUBAC活性可能是骨髓性白血病的有效治疗靶点。
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 ofHoipand 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 bothHoip-deficient hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) impaired the maintenance of quiescence, conditional deletion ofHoipinduced 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.