AbstractKMT2A-rearranged acute lymphoblastic leukemia (ALL) is characterized by deregulation of the epigenome and shows susceptibility towards histone deacetylase (HDAC) inhibition. Most broad-spectrum HDAC inhibitors simultaneously target multiple human HDAC isoforms. Consequently, they often induce toxicity and especially in combination with other therapeutic agents.

摘要KMT2A重排急性淋巴细胞白血病（ALL）的特征是表观基因组失调，并显示出对组蛋白脱乙酰酶（HDAC）抑制的敏感性。大多数广谱HDAC抑制剂同时靶向多种人类HDAC同种型。因此，它们通常会引起毒性，尤其是与其他治疗剂联合使用。

Therefore, more specifically targeting HDAC isoforms may represent a safer therapeutic strategy. Here we show that shRNA-mediated knock-down of the class IIA HDAC isoforms HDAC4, HDAC5, and HDAC7 results in apoptosis induction and cell cycle arrest in KMT2A-rearranged ALL cells. In concordance, the HDAC4/5 selective small molecule inhibitor LMK-235 effectively eradicates KMT2A-rearranged ALL cell lines as well as primary patient samples in vitro.

因此，更具体地靶向HDAC同种型可能代表更安全的治疗策略。在这里，我们显示shRNA介导的II a类HDAC亚型HDAC4，HDAC5和HDAC7的敲低导致KMT2A重排的ALL细胞中的凋亡诱导和细胞周期停滞。一致地，HDAC4/5选择性小分子抑制剂LMK-235在体外有效地根除了KMT2A重排的所有细胞系以及原发性患者样品。

However, using a xenograft mouse model of KMT2A-rearranged ALL we found that the maximum achievable dose of LMK-235 was insufficient to induce anti-leukemic effects in vivo. Similar results were obtained for the specific class IIA HDAC inhibitors MC1568 and TMP195. Finally, LMK-235 appeared to exert minimal anti-leukemic effects in vivo in combination with the BCL-2 inhibitor venetoclax, but not enough to prolong survival in treated mice.

。对于特定的II a类HDAC抑制剂MC1568和TMP195，获得了类似的结果。最后，LMK-235似乎与BCL-2抑制剂venetoclax联合在体内发挥最小的抗白血病作用，但不足以延长治疗小鼠的存活期。

In conclusion, class IIA HDAC isoforms represent attractive therapeutic target in KMT2A-rearranged ALL, although clinical applications require the development of more stable and efficient specific HDAC inhibitors..

总之，II a类HDAC亚型代表了KMT2A重排ALL中有吸引力的治疗靶点，尽管临床应用需要开发更稳定和有效的特异性HDAC抑制剂。。

IntroductionAcute lymphoblastic leukemia (ALL) in infants ( < 1 year of age at diagnosis) is a rare but highly aggressive type of leukemia in which ~80% of cases is driven by chromosomal translocations of the KMT2A gene (encoding Lysine methyltransferase 2 A). Translocations of the KMT2A gene on chromosome 11q23 lead to fusions of the N-terminus of KMT2A to the C-terminus of one of many known fusion partners.

引言婴儿急性淋巴细胞白血病（ALL）（诊断时小于1岁）是一种罕见但高度侵袭性的白血病类型，其中约80%的病例是由KMT2A基因（编码赖氨酸甲基转移酶2A）的染色体易位驱动的。染色体11q23上KMT2A基因的易位导致KMT2A的N端融合到许多已知融合伴侣之一的C端。

In infant ALL, KMT2A is most recurrently fused to either AFF1 (49% of the cases), MLLT1 (22% of the cases) or MLLT3 (16% of the cases)1,2. The event-free survival (EFS) rates for infant ALL patients without KMT2A translocations is 75-80%, whereas the EFS of KMT2A-rearranged infant ALL patients still remains 40%3,4,5, urging the need for more effective treatment strategies.The three most recurring KMT2A fusion proteins (i.e.

在婴儿ALL中，KMT2A最常与AFF1（49%的病例），MLLT1（22%的病例）或MLLT3（16%的病例）1,2融合。没有KMT2A易位的婴儿ALL患者的无事件生存率（EFS）为75-80%，而KMT2A重排的婴儿ALL患者的EFS仍然为40%3,4,5，这促使需要更有效的治疗策略。三种最常见的KMT2A融合蛋白（即。

AFF1, MLLT1, MLLT3) hijack the transcriptional elongation machinery, thereby rewriting the transcriptomic and epigenetic landscape of the cell, KMT2A-rearranged ALL cells are often sensitive to epigenetic inhibitors6,7,8. A well-known class of epigenetic-based drugs are histone deacetylase (HDAC) inhibitors, which are able to reverse the acetylation status of histones as well as a variety of non-histone proteins9,10.

AFF1，MLLT1，MLLT3）劫持转录延伸机制，从而重写细胞的转录组和表观遗传景观，KMT2A重排的所有细胞通常对表观遗传抑制剂敏感6,7,8。一类众所周知的基于表观遗传的药物是组蛋白脱乙酰酶（HDAC）抑制剂，它能够逆转组蛋白以及各种非组蛋白的乙酰化状态9,10。

The most commonly used and extensively studied HDAC inhibitors (HDACi) are non-selective compounds targeting a wide variety of HDAC isoforms or complete classes simultaneously11,12,13. Previous pre-clinical work from our laboratory demonstrated pronounced in vivo anti-leukemic activity of the broad-spectrum HDAC inhibitor Panobinostat (LBH589) in patient-derived xenograft (PDX) mouse models of KMT2A-rearranged infant ALL14.

最常用和广泛研究的HDAC抑制剂（HDACi）是同时靶向多种HDAC同种型或完整类别的非选择性化合物11,12,13。我们实验室先前的临床前工作表明，广谱HDAC抑制剂Panobinostat（LBH589）在KMT2A重排婴儿ALL14的患者来源的异种移植（PDX）小鼠模型中具有明显的体内抗白血病活性。

Unfortunately, additional experiments combining Panobinostat with other agents showed high levels of toxicity .

不幸的是，将Panobinostat与其他药物结合的其他实验显示出高水平的毒性。

Data availability

数据可用性

All data associated with this study are present in this paper or the Supplementary Information. All source data behind each graph are shown in Supplementary Data 1. All other data are available from the corresponding author on reasonable request.

与本研究相关的所有数据均存在于本文或补充信息中。每个图表后面的所有源数据都显示在补充数据1中。所有其他数据均可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsWe thank the members of the Stam group at the Princess Máxima Center for advice and discussions. We would like to thank the people from the Preclinical Intervention Unit of the Mouse Clinic for Cancer and Ageing (MCCA) at the Netherlands Cancer Institute for performing the PK/PD study.

下载参考文献致谢我们感谢Máxima公主中心Stam小组成员的建议和讨论。我们要感谢荷兰癌症研究所癌症与衰老小鼠诊所（MCCA）临床前干预部门的人员进行PK/PD研究。

We would like to thank the people from the Preclinical Imaging Center (PRIME) unit from the Animal Research Facility at the Radboud UMC Nijmegen for biotechnical support of the in vivo studies. This work was financially supported by Stichting Kinderen Kankervrij (KiKa-236), Dutch Cancer Society (KWF-11863) and a Princess Máxima Center PhD grant.Author informationAuthors and AffiliationsPrincess Máxima Center, Utrecht, The NetherlandsTamara C.

我们要感谢Radboud UMC奈梅亨动物研究机构的临床前成像中心（PRIME）部门的人员对体内研究的生物技术支持。这项工作得到了Stichting Kinderen Kankervrij（KiKa-236），荷兰癌症协会（KWF-11863）和公主Máxima中心博士学位授予的财政支持。作者信息作者和附属机构荷兰乌得勒支Máxima中心。

A. I. Verbeek, Kirsten S. Vrenken, Susan T. C. J. M. Arentsen-Peters, Patricia Garrido Castro, Rob Pieters & Ronald W. StamNetherlands Cancer Institute, Amsterdam, The NetherlandsMarieke van de Ven & Olaf van TellingenAuthorsTamara C. A. I. VerbeekView author publicationsYou can also search for this author in.

A、 I.Verbeek，Kirsten S.Vrenken，Susan T.C.J.M.Arentsen Peters，Patricia Garrido Castro，Rob Pieters＆Ronald W.StamNetherlands癌症研究所，阿姆斯特丹，NetherlandsMarieke van de Ven＆Olaf van Tellingauthors Tamara C.A.I.VerbeekView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsT.V. designed and performed research, analysed data and wrote the manuscript. K.V. designed and performed research, contributed to the pLNT vector and reviewed the manuscript. S.A.P., P.G.C. designed and performed research and analysed data. M.V., O.T.

PubMed谷歌学术贡献者。五、 设计并进行研究，分析数据并撰写手稿。K、 V.设计并进行了研究，为pLNT载体做出了贡献，并审阅了手稿。S、 A.P.，P.G.C.设计并进行了研究和分析数据。M、 V.，O.T。

designed and performed PK/PD study for LMK-235. R.S., R.P. supervised the project, designed and interpreted the research and wrote the manuscript. All authors critically reviewed the manuscript and approved the final version.Corresponding authorCorrespondence to.

设计并进行了LMK-235的PK/PD研究。R、 S.，R.P.监督该项目，设计和解释研究并撰写手稿。所有作者都严格审查了稿件并批准了最终版本。对应作者对应。

Ronald W. Stam.Ethics declarations

罗纳德·W·斯塔姆。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethical approval

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All animal experiments, if not stated differently, were carried out according to Dutch legislation and approved by the Animal Ethics Committee (Approval Number: AVD3990020173066 & AVD39900202216167) at the Princess Máxima Center, Utrecht, The Netherlands. The pharmacokinetics study for LMK-235 was approved by the Animal Ethics Committee (Approval Number: AVD301002016407) at the Netherlands Cancer Institute, Amsterdam, The Netherlands..

所有动物实验，如果没有不同的说明，都是根据荷兰法律进行的，并得到了荷兰乌得勒支公主Máxima中心动物伦理委员会（批准号：AVD3990020173066和AVD399002216167）的批准。LMK-235的药代动力学研究得到了荷兰阿姆斯特丹荷兰癌症研究所动物伦理委员会（批准号：AVD301002016407）的批准。。

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Peer review information

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Communications Biology thanks Cristina Pina, Naroa Gimenez and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Toril Holien and Mengtan Xing. A peer review file is available.

《传播生物学》感谢克里斯蒂娜·皮纳（CristinaPina）、纳罗亚·吉梅内兹（NaroaGimenez）和另一位匿名审稿人对这项工作的同行评议做出的贡献。主要负责编辑：托利·霍利恩（TorilHolien）和孟坦兴（MengtanXing）。同行评审文件可用。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationPeer Review FileSupplementary InformationDescription of Additional Supplementary MaterialsSupplementary Data 1Rights and permissions.

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Reprints and permissionsAbout this articleCite this articleVerbeek, T.C.A.I., Vrenken, K.S., Arentsen-Peters, S.T.C.J.M. et al. Selective inhibition of HDAC class IIA as therapeutic intervention for KMT2A-rearranged acute lymphoblastic leukemia.

转载和许可本文引用本文Verbeek，T.C.A.I.，Vrenken，K.S.，Arentsen-Peters，S.T.C.J.M.等人选择性抑制HDAC II A类作为KMT2A重排急性淋巴细胞白血病的治疗干预。

Commun Biol 7, 1257 (2024). https://doi.org/10.1038/s42003-024-06916-wDownload citationReceived: 12 March 2024Accepted: 17 September 2024Published: 04 October 2024DOI: https://doi.org/10.1038/s42003-024-06916-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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