Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein.
Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein.
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免疫蛋白酶体抑制剂ONX-0914在表达MLL-AF4融合蛋白的急性淋巴细胞白血病中的活性。
DOI：
10.1038/s41598-021-90451-9
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发表时间：
2021-05-25
影响因子：
4.6
通讯作者：
Kisselev AF
中科院分区：
文献类型：
--
作者：
Jenkins TW;Downey-Kopyscinski SL;Fields JL;Rahme GJ;Colley WC;Israel MA;Maksimenko AV;Fiering SN;Kisselev AF
蛋白酶体抑制剂Bortezomib和carfilzomib被批准用于治疗多发性骨髓瘤和套细胞淋巴瘤，并已证明对急性淋巴细胞白血病(ALL)具有临床疗效。T(4；11)(q21；q23)染色体易位导致MLL-AF4融合蛋白表达，预后不良，是婴幼儿ALL的主要原因。这种易位使肿瘤细胞对蛋白酶体抑制剂敏感，但硼替佐米和卡菲佐米的毒性可能会限制它们在儿科患者中的使用。其中许多毒性是由于靶向抑制非淋巴组织(如心肌、肠道、睾丸)中的蛋白酶体引起的。我们发现，MLL-AF4细胞表达高水平的淋巴组织特异性免疫蛋白酶体，并且即使在基质细胞存在的情况下，也对药物相关浓度的特定免疫蛋白酶体抑制剂ONX-0914敏感。需要抑制免疫蛋白酶体的多个活性部位才能实现对ALL的细胞毒作用。免疫蛋白酶体LMP7(？5i)和LMP2(？1i)位点的抑制剂ONX-0914和蛋白酶体？2位点的抑制剂LU-102具有协同的细胞毒作用。ONX-0914治疗显著延缓了小鼠原位ALL移植瘤的生长。T细胞株对药理上相关浓度的ONX-0914也很敏感。这项研究为临床阶段免疫蛋白酶体抑制剂KZ-616和M3258在ALL中的检测提供了强有力的理论基础。
Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL–AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL–AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (ß5i) and LMP2 (ß1i) sites of the immunoproteasome, and LU-102, inhibitor of proteasome ß2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL.
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影响因子：
3.7
作者：
Eriksson E;Zaman F;Chrysis D;Wehtje H;Heino TJ;Sävendahl L
通讯作者：
Sävendahl L
影响因子：
7.3
作者：
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通讯作者：
Kisselev, Alexei F.
影响因子：
82.9
作者：
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通讯作者：
Groettrup, Marcus
影响因子：
20.3
作者：
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通讯作者：
Bourquin, Jean-Pierre
影响因子：
16.6
作者：
de Bruin, Gerjan;Xin, Bo Tao;Overkleeft, Herman S.
通讯作者：
Overkleeft, Herman S.