Mubritinib 靶向电子传输链复合物 I 并揭示急性髓性白血病中线粒体易损性的情况,Blood

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Mubritinib 靶向电子传输链复合物 I 并揭示急性髓性白血病中线粒体易损性的情况
Blood ( IF 21.0 ) Pub Date : 2018-11-29 , DOI: 10.1182/blood-2018-99-114525
Irene Baccelli ₁ , Yves Gareau ₂ , Bernhard Lehnertz ₃ , Gingras Stephane ₄ , Jean-Francois Spinella ₅ , Alexandre Beautrait ₄ , Sophie Corneau ₁ , Nadine Mayotte ₁ , Isabel Boivin ₁ , Simon Girard ₁ , Tara MacRae ₁ , Melanie Frechette ₁ , Koryne Leveille ₁ , Jana Krosl ₁ , Clarisse Thiollier ₁ , Evgeny Kanshin ₃ , Thierry Bertomeu ₃ , Jasmin Coulombe-Huntington ₃ , Corinne St-Denis ₃ , Marie-Eve Bordeleau ₁ , Geneviève Boucher ₁ , Philippe P Roux ₃ , Sébastien Lemieux _{5,

6} , Mike Tyers ₃ , Pierre Thibault ₃ , Anne Marinier ₅ , Josée Hébert _{1,

7} , Guy Sauvageau _{3,

8,

9}

Affiliation

摘要背景：60%～70%的急性髓系白血病（AML）患者在诱导治疗后进入完全缓解期，但由于耐药性白血病干细胞（LSCs）的生长，大多数在3年内复发。因此，确定对这些细胞有效的新治疗策略代表了一项突出的医疗需求。我们开发了一种细胞培养方法，它可以在体外瞬时维持 LSC 活性（Pabst 等人，Nature Methods，2014），并能够对与疾病进展相关的细胞类型进行化学询问。总体而言，HSC 和 LSC 具有许多共同的生物学特征，使得特定 LSC 的根除具有挑战性。然而，最近有人提出了正常和白血病干细胞之间能量代谢的显着差异。虽然 HSCs 似乎主要依赖于无氧糖酵解来产生能量，但 LSCs 似乎依赖于线粒体氧化磷酸化来生存。因此，针对线粒体呼吸可以代表一种特定根除 LSC 的有效方法。目的：我们旨在为治疗结果不佳的 AML 确定新的治疗靶点。该研究依赖于 Leucegene 方法，该方法整合了原发性人类 AML 样本的 RNA 测序分析产生的结果、魁北克白血病细胞库提供的详细临床和细胞遗传学注释以及原发性 AML 样本对各种化合物的离体反应。我们的研究特别关注来自较差（总生存期< 3 年）和良好（总生存期 ≥ 3 年）对标准化疗的反应，不包括急性早幼粒细胞白血病 (APL) 病例。结果：我们将先前描述为 ERBB2 抑制剂的 Mubritinib 鉴定为一种新型抗白血病药物，它选择性地抑制来自耐药性 AML 患者的白血病细胞的活力，但不影响正常的 CD34+ 脐带血细胞。在具有高线粒体功能相关基因表达、高复发率和短总生存期的 AML 样本子集中，暴露于 Mubritinib 引发了凋亡细胞死亡。对 Mubritinib 的敏感性还与中等细胞遗传学风险类别、正常核型 (NK) 和 NPM1、FLT3 (ITD) 和 DNMT3A 突变密切相关。相反，对 Mubritinib 的耐药性与有利的细胞遗传学风险 AML 相关，核心 Binging 因子 (CBF) 白血病和 KIT 突变。Mubritinib 已被开发为 ERBB2 激酶抑制剂。有趣的是，我们发现 ERBB2 在 Mubritinib 敏感的 AML 标本中不表达，这表明该化合物的抗白血病活性可能不是由 ERBB2 抑制介导的。结合功能基因组学和生化分析，我们证明 Mubritinib 直接抑制线粒体电子传输链 (ETC) 复合物 I，从而导致氧化磷酸化活性降低并诱导氧化应激。使用同系小鼠模型（MLL-AF9 tdTomato 阳性白血病）探索了 Mubritinib 对 AML 进展的影响。与对照小鼠相比，接受 Mubritinib 治疗的 MLL-AF9 细胞受体的骨髓中 tdTomato 阳性细胞数量减少了 19 倍，脾脏减少了 42 倍。与载体治疗的小鼠相比，短期治疗还导致暴露于 Mubritinib 的接受者的中位总生存期增加 37%。重要的是，与我们观察到的 Mubritinib 治疗不会阻碍体外正常造血 CD34+ 细胞的增殖一致，Mubritinib 治疗对受体的非转导（tdTomato 阴性）有核骨髓细胞的数量没有影响。结论：我们发现了临床、突变、和 AML 中线粒体易损性的转录景观，并确定 Mubritinib 是一种新型 ETC 复合物 I 抑制剂，对目前缺乏有效治疗选择的大约 30% 的 AML 病例具有治疗潜力。由于 Mubritinib 在 ERBB2 阳性实体瘤的背景下完成了 I 期临床试验，我们的工作表明有机会将 Mubritinib 重新用于这一基因不同的不良结果 AML 患者亚组。披露没有需要声明的相关利益冲突。s 用于这种遗传上不同的不良结果 AML 患者亚组。披露没有需要声明的相关利益冲突。s 用于这种遗传上不同的不良结果 AML 患者亚组。披露没有需要声明的相关利益冲突。

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Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of Mitochondrial Vulnerability in Acute Myeloid Leukemia

Abstract BACKGROUND: 60% to 70% of Acute Myeloid Leukemia (AML) patients enter complete remission after induction regimen, but the majority relapse within 3 years due to the outgrowth of therapy resistant Leukemia Stem Cells (LSCs). Identification of novel treatment strategies effective against these cells thus represents an outstanding medical need. We developed a cell culture method, which transiently maintains LSC activity ex vivo (Pabst et al., Nature Methods, 2014) and enables chemical interrogation of cell types relevant for the progression of the disease. Overall, HSCs and LSCs share numerous biological traits, making specific LSC eradication challenging. However, striking differences in energy metabolism between normal and leukemic stem cells have recently been suggested. While HSCs appear to rely primarily on anaerobic glycolysis for energy production, LSCs seem to depend on mitochondrial oxidative phosphorylation for their survival. Targeting mitochondrial respiration could therefore represent an effective approach for the specific eradication of LSCs. AIM: We aimed to identify novel therapeutic targets for AMLs with poor treatment outcome. The study relied on the Leucegene approach that integrates results generated by RNA sequencing analysis of primary human AML specimens, detailed clinical and cytogenetic annotations provided by the Quebec leukemia cell bank and ex vivo responses of primary AML samples to various chemical compounds. Our study specifically focused on specimens originating from patients with poor (overall survival < 3 years) and good (overall survival ≥ 3 years) response to standard chemotherapy, and did not include cases of Acute Promyelocytic Leukemia (APL). RESULTS: We identified Mubritinib, previously described as an ERBB2 inhibitor, as a novel anti-leukemic agent, which selectively inhibits the viability of leukemic cells from therapy-resistant AML patients, but does not affect normal CD34+ cord blood cells. Exposure to Mubritinib triggered apoptotic cell death in a subset of AML samples with high mitochondrial function-related gene expression, high relapse rates, and short overall survival. Sensitivity to Mubritinib also strongly associated with the intermediate cytogenetic risk category, normal karyotype (NK), and NPM1, FLT3 (ITD) and DNMT3A mutations. Conversely, resistance to Mubritinib associated with favorable cytogenetic risk AMLs, Core Binging Factor (CBF) leukemias and KIT mutations. Mubritinib has been developed as an ERBB2 kinase inhibitor. Intriguingly, we found that ERBB2 is not expressed in Mubritinib-sensitive AML specimens, suggesting that the anti-leukemic activity of this compound is likely not mediated by ERBB2 inhibition. Using a combination of functional genomics and biochemical analyses, we demonstrated that Mubritinib directly inhibits the mitochondrial Electron Transport Chain (ETC) complex I, which leads to a decrease in oxidative phosphorylation activity and to induction of oxidative stress. The impact of Mubritinib on AML progression was explored using a syngeneic mouse model (MLL-AF9 tdTomato-positive leukemia). Recipients of MLL-AF9 cells treated with Mubritinib exhibited a 19-fold decrease in the number of tdTomato-positive cells in the bone marrow and a 42-fold decrease in the spleens compared to control mice. Short-term treatment also led to a 37% increase in the median overall survival of Mubritinib exposed recipients compared to vehicle treated mice. Importantly, and in agreement with our observation that Mubritinib treatment does not impede proliferation of normal hematopoietic CD34+ cells in vitro, Mubritinib treatment had no impact on the number of non-transduced (tdTomato negative) nucleated bone marrow cells of recipients. CONCLUSIONS: We uncovered the clinical, mutational, and transcriptional landscape of mitochondrial vulnerability in AML and identified Mubritinib as a novel ETC complex I inhibitor with therapeutic potential for approximately 30% of AML cases currently lacking effective treatment options. As Mubritinib completed a phase I clinical trial in the context of ERBB2-positive solid tumors, our work suggests an opportunity to re-purpose Mubritinib's usage for this genetically distinct subgroup of poor outcome AML patients. Disclosures No relevant conflicts of interest to declare.

更新日期：2018-11-29

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