Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates < 40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.

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Published in Nature Communications, v. 10, article no. 2189, p. 1-16.

© The Author(s) 2019

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital, OSU Comprehensive Cancer Center Pelotonia Funds, National Institutes of Health Cancer Center Support Grant P30 CA021765 (SJCRH), P30 CA016058 (OSUCCC), R01 CA138744 (S.D.B.), and F32 CA180513 (C.D.D.).

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The RNA-seq data generated and analyzed in this study are available at the Gene Expression Omnibus (GEO) repository of the National Center for Biotechnology Information under accession code GSE126489. The authors declare that all data generated from this study are included in this publication and its Supplementary Information, Source Data file (Figs. 2–7; Supplementary Figs. 1, 3, 5, 7, 9, 13, 15, 16), or available from the corresponding author on request.

The Pipeline Pilot protocol (exported as a Pipeline Pilot formatted xml file), including the embedded R code, are reported in Supplementary Software.

Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467- 019-09917-0.

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Supplementary Information

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Description of Additional Supplementary Files

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Supplementary Data 1

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Supplementary Data 2

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Supplementary Software