AbstractTargeted therapeutics for high-risk cancers remain an unmet medical need. Here we report the results of a large-scale screen of over 11,000 molecules for their ability to inhibit the survival and growth in vitro of human leukemic cells from multiple sources including patient samples, de novo generated human leukemia models, and established human leukemic cell lines.

摘要针对高危癌症的靶向治疗仍然是未满足的医疗需求。在这里，我们报告了超过11000个分子的大规模筛选结果，这些分子能够抑制来自多种来源的人类白血病细胞的体外存活和生长，包括患者样品，从头生成的人类白血病模型和已建立的人类白血病细胞系。

The responses of cells from de novo models were most similar to those of patient samples, both of which showed striking differences from the cell-line responses. Analysis of differences in subtype-specific therapeutic vulnerabilities made possible by the scale of this screen enabled the identification of new specific modulators of apoptosis, while also highlighting the complex polypharmacology of anti-leukemic small molecules such as shikonin.

从头模型的细胞反应与患者样品的反应最相似，两者均显示出与细胞系反应的显着差异。通过该筛选的规模分析亚型特异性治疗脆弱性的差异，可以鉴定新的特异性细胞凋亡调节剂，同时也突出了抗白血病小分子如紫草素的复杂多药理学。

These findings introduce a new platform for uncovering new therapeutic options for high-risk human leukemia, in addition to reinforcing the importance of the test sample choice for effective drug discovery..

这些发现为揭示高危人类白血病的新治疗选择提供了一个新的平台，此外还加强了测试样本选择对有效药物发现的重要性。。

IntroductionThe development of targeted treatments for high-risk pediatric acute leukemias, including acute myeloid leukemia (AML) [1], and acute megakaryoblastic leukemia (AMKL) [2] remains an important unmet medical need. Interestingly, although the phenotypic classification of pediatric and adult leukemia is similar, recent large-scale sequencing studies have highlighted striking differences in the genetic drivers and cells of origin of the disease between the two age groups [3, 4].

引言针对高危儿童急性白血病（包括急性髓细胞白血病（AML）和急性巨核细胞白血病（AMKL））的靶向治疗的发展仍然是一个重要的未满足的医疗需求。有趣的是，尽管小儿和成人白血病的表型分类相似，但最近的大规模测序研究强调了两个年龄组之间疾病的遗传驱动因素和起源细胞的显着差异[3，4]。

Analysis of the genomes of adult AML samples, which were among the first cancer genomes to be fully sequenced [5], revealed recurrent mutations in a heterogeneous collection of genes including DNMT3a, IDH1/2, NPM1 and FLT3 [6]. In contrast, highly heterogeneous gene fusions created by chromosomal rearrangements, have been found to be more characteristic of pediatric leukemias [4].

成人AML样本的基因组分析是首批被完全测序的癌症基因组之一，揭示了DNMT3a、IDH1/2、NPM1和FLT3等异质基因集合中的复发突变。相比之下，由染色体重排产生的高度异质性基因融合已被发现是小儿白血病的更多特征（4）。

For, example, translocations of KMT2A seen in both AML and AMKL have been found to involve over 130 partner genes that have prognostic significance for patient survival [7], although most confer a poor prognosis similar to NUP98::KDM5A and CBFA2T3::GLIS2 fusion genes associated with AMKL [2]. This multiplicity of genetic alterations seen in leukemia has undermined efforts to develop effective genetically based drugs and has largely limited improvements in outcomes in AML/AMKL to more refined risk stratification and supportive care strategies.Although standard chemotherapeutic regimens can be effective in some patients, these non-targeted treatments also result in significant and life-long side effects.

例如，在AML和AMKL中发现的KMT2A易位涉及130多个对患者生存具有预后意义的伴侣基因（7），尽管大多数预后不佳，类似于NUP98：：KDM5A和CBFA2T3：：GLIS2与AMKL相关的融合基因（2）。白血病中出现的这种多样的基因改变破坏了开发有效的基于基因的药物的努力，并且在很大程度上限制了AML/AMKL结局的改善，从而限制了更精细的风险分层和支持性护理策略。尽管标准化疗方案对某些患者可能有效，但这些非靶向治疗也会导致显着的终身副作用。

This limitation has motivated efforts to identify alternative approaches for specifically eradicating leukemia cells. While detailed genetic and biochemical studies can be undertaken to identify leukemia-specific .

这种限制促使人们努力确定特异性根除白血病细胞的替代方法。虽然可以进行详细的遗传和生化研究以鉴定白血病特异性。

Data availability

数据可用性

All sequencing data for this manuscript has been deposited to GEO and is accessible through the following accession numbers: GSE207798. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD040772 and 10.6019/PXD040772..

。质谱蛋白质组学数据已通过PRIDE合作伙伴存储库保存到ProteomeXchange Consortium，数据集标识符为PXD040772和10.6019/PXD040772。。

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Download referencesAcknowledgementsThis work was supported by grants from the Cole Foundation (V.G. fellowship), Oncopole (EMC2 grant through the Fonds de recherche du Québec – Santé (FRQS), Génome Québec, the Cancer Research Society, and IRICoR (B.T.W., F.B., S.C., A.M., J.H., K.E., G.S.), the Canadian Cancer Society Impact grant #705047 in collaboration with The Cole Foundation, Molson Foundation, R.

下载参考文献致谢这项工作得到了科尔基金会（V.G.fellowship），Oncopole（通过魁北克-桑特研究基金会（FRQS）的EMC2资助），魁北克省基因组学，癌症研究协会和IRICoR（B.T.W.，F.B.，S.C.，A.M.，J.H.，K.E.，G.S。），加拿大癌症协会影响基金会（705047）与科尔基金会，莫尔森基金会，R。

Howard Webster Foundation, Mirella and Lino Saputo Foundation, Fonds de recherche du Quebec - Santé, Faculté de médicine, Université de Montréal, Letko Brosseau, Birks Family Foundation, Maryse and William Brock, CHU Sainte-Justine Foundation, Montreal Children’s Hospital Foundation, Morris and Rosalind Goodman Family Foundation, Zeller Family Foundation, David H.

霍华德·韦伯斯特基金会、米雷拉和利诺·萨普托基金会、魁北克圣徒研究基金会、医学院、蒙特利尔大学、莱特科·布罗索、伯克斯家庭基金会、玛丽·丝和威廉·布罗克、朱圣·贾斯汀基金会、蒙特利尔儿童医院基金会、莫里斯和罗莎琳德·古德曼家庭基金会、泽勒家庭基金会、大卫·H。

Laidley Foundation, Drummond Foundation, and the Henry and Berenice Kaufmann Foundation (grant 705047-IMP-17; B.T.W., F.B., S.C.), the Leukemia & Lymphoma Society of Canada (to F.B.), Terry Fox Foundation Program Project grant (TFF#1074) funding to CE, a FRSQ J1 salary award (G.D.), an operating grant from the Cancer Research Society (G.D.), the Canadian Institutes of Health Research (grant FRN 178326; S.C.), the CHU Sainte-Justine Foundation (Fonds d’Innovation Thérapeutique; S.C.), and the Charles-Bruneau Foundation (supporting humanized mouse core and flow cytometry facilities at CHU Sainte-Justine).

莱德利基金会、德拉蒙德基金会、亨利和贝雷妮斯·考夫曼基金会（grant 705047-IMP-17；B.T.W.，F.B.，S.C.）、加拿大白血病和淋巴瘤协会（F.B.）、特里·福克斯基金会项目资助（TFF#1074）CE、FRSQ J1工资奖（G.D.）、癌症研究学会（G.D.）的运营资助、加拿大卫生研究院（grant FRN 178326；S.C.）、朱圣·贾斯汀基金会（Fonds D'Innovation Thérapeutique；S.C.）和查尔斯布鲁诺基金会（支持CHU Sainte Justine的人性化小鼠核心和流式细胞仪设施）。

S.C. is the recipient of a Clinician Scientist senior award from the FRQS. We are grateful to the patients who provided biospecimens for these studies to the OSU Comprehensive Cancer Center Hematology Tissue Bank Shared Resource (supported by NIH NCI P30 CA016058). Human leukemia specimens were collected and analyzed by the Banque de cellules leucémiques du Québec (BCLQ), supported by the Cancer R.

S、 C.是FRQS颁发的临床医生-科学家高级奖的获得者。我们感谢向OSU综合癌症中心血液学组织库共享资源（由NIH NCI P30 CA016058支持）提供这些研究的生物样本的患者。人类白血病标本由魁北克细胞白血病研究所（BCLQ）收集和分析，由癌症研究所支持。

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PubMed Google ScholarContributionsSC, FB and BTW conceptualized the study with input from GS and AM Small molecule screening was performed by ER, FBM, VG, KPM, IB, JD, and SM and screening data analysis was performed by SSTH with assistance from BTW. Validation studies for individual compounds were performed by VG, KPM, with assistance from MB and FBM and NH for additional analysis.

PubMed Google ScholarContributionsSC，FB和BTW概念化了来自GS和AM的输入的研究小分子筛选由ER，FBM，VG，KPM，IB，JD和SM进行，筛选数据分析由SSTH在BTW的帮助下进行。单个化合物的验证研究由VG，KPM进行，MB和FBM以及NH协助进行额外分析。

Proteomic studies and analysis were performed by CMP and EB with assistance from FBM, and supervised by PT. Metabolomics studies were performed by GA and KPM, and supervised by GD. Leukemic stem cell studies were performed by IL with supervision by KE. Model leukemia samples were generated by ACS, EB, ES, VG, SCa, MB, and PDX generation was performed by SCa, NN and supervised by CJE and patient samples were characterized by JH.

蛋白质组学研究和分析由CMP和EB在FBM的协助下进行，由PT监督。代谢组学研究由GA和KPM进行，由GD监督。白血病干细胞研究由IL进行，由KE监督。模型白血病样品由ACS，EB，ES，VG，SCa，MB产生，PDX产生由SCa，NN进行，由CJE监督，患者样品由JH表征。

The original draft was written by SSTH, and all co-authors reviewed and edited the manuscript.Corresponding authorsCorrespondence to.

原稿由SSTH撰写，所有合著者均审阅并编辑了手稿。通讯作者通讯。

Sonia Cellot, Frédéric Barabé or Brian T. Wilhelm.Ethics declarations

索尼娅·塞洛特（SoniaCellot）、弗里德里克·巴拉贝（FrédéricBarabé）或布莱恩·威廉（BrianT.Wilhelm）。道德宣言

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Reprints and permissionsAbout this articleCite this articleSafa-Tahar-Henni, S., Páez Martinez, K., Gress, V. et al. Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines.

转载和许可本文引用本文Safa Tahar Henni，S.，Páez Martinez，K.，Gress，V。等人。原发性人类急性白血病，工程化人类白血病和白血病细胞系的比较小分子筛选。

Leukemia (2024). https://doi.org/10.1038/s41375-024-02400-wDownload citationReceived: 12 December 2023Revised: 14 July 2024Accepted: 28 August 2024Published: 29 October 2024DOI: https://doi.org/10.1038/s41375-024-02400-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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