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Leukemia-propagating cells demonstrate distinctive gene expression profiles compared with other cell fractions from patients with de novo Philadelphia chromosome-positive ALL

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Abstract

Relapse remains one of the major obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) even after allogeneic hematopoietic stem cell transplantation. The persistence of leukemia-propagating cells (LPCs) may lead to the recurrence of Ph+ALL. Using a xenograft assay, LPCs enrichment in the CD34+CD38−CD58− fraction in Ph+ALL was recently identified. A further cohort study indicated that the LPCs phenotype at diagnosis was an independent risk factor for relapse of Ph+ALL. However, little is known about the potential molecular mechanism of LPCs-mediated relapse. Therefore, the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL were investigated using RNA sequencing (RNA-Seq). Most of the differentially expressed genes between the LPCs and other cell fractions were related to the regulation of the cell cycle and metabolism, as identified by the gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Consistent with the RNA-Seq results, the mRNA levels of cell cycle-related genes, such as cyclin-dependent kinase 4, were significantly lower in the LPCs fraction than in other cell fractions. Moreover, the proportion of quiescent cells in LPCs was significantly higher than in other cell fractions. In summary, distinctive gene expression profiles and clusters, which were mostly related to the regulation of the cell cycle and metabolism, were demonstrated between LPCs and other cell fractions from patients with de novo Ph+ALL. Therefore, it would be beneficial to develop novel LPCs-based therapeutic strategies for Ph+ALL patients.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant nos. 81570127&81370638&81530046), Milstein Medical Asian American Partnership (MMAAP) Foundation, the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81621001), Beijing Municipal Science and Technology Program (Z151100004015164), and the Science and Technology Project of Guangdong Province of China (2016B030230003). American Journal Experts (www.journalexperts.com) provided editorial assistance to the authors during the preparation of the manuscript. The authors thank all of the core facilities at Peking University Institute of Hematology for sample collection.

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  1. Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China

    Hong-Yan Zhao, Yang Song, Xie-Na Cao, Ya-Zhen Qin, Yue-Yun Lai, Hao Jiang, Qian Jiang, Xiao-Jun Huang & Yuan Kong

  2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Yang Song & Xiao-Jun Huang

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  1. Hong-Yan Zhao
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This study was approved by the Ethics Committee of Peking University People’s Hospital (reference number: 2015PHB214-01). Informed consent was obtained from all patients and donors before entry into the study in accordance with the Declaration of Helsinki.

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Zhao, HY., Song, Y., Cao, XN. et al. Leukemia-propagating cells demonstrate distinctive gene expression profiles compared with other cell fractions from patients with de novo Philadelphia chromosome-positive ALL. Ann Hematol 97, 799–811 (2018). https://doi.org/10.1007/s00277-018-3253-5

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