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Acute myeloid leukemia

Mutant p53 enhances leukemia-initiating cell self-renewal to promote leukemia development

Leukemia volume 33, pages 1535–1539 (2019)Cite this article

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Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis [1]. AML is thought to be initiated and maintained by a rare population of leukemia stem cells (LSCs) or leukemia-initiating cells (LICs) that have acquired the capacity for self-renewal and is blocked in their ability to differentiate by the accumulation of a series of mutations and/or epigenetic changes [2, 3]. Clinical studies show that LICs are resistant to conventional chemotherapy and/or targeted therapies [3]. Thus, there is an unmet need to elucidate the molecular mechanisms governing LIC self-renewal and develop novel therapeutic approaches that can target LICs and improve leukemia treatment [3].

The tumor suppressor p53 is a stress response protein that regulates a large number of genes in response to a variety of cellular insults, including oncogene activation, DNA damage, and inflammation [4]. These signals activate p53 primarily through post-translational modifications that result in augmented levels of p53 protein and transactivation activity [4]. Activated p53 suppresses cellular transformation mainly by inducing growth arrest, apoptosis, DNA repair, and differentiation in damaged cells [4]. Accordingly, p53 function is always compromised in tumor cells, usually as a result of somatic mutations and deletions, which occur in approximately half of all human cancers [5]. The TP53 gene encodes the tumor suppressor p53. The frequency of TP53 mutations in AML is ~10%. However, in AML with complex karyotype, the frequency of TP53 mutations and/or deletions is almost 70% [6]. While TP53 mutations confer drug resistance and poor prognosis in AML, the role of mutant p53 in the initiation and progression of AML is largely unknown [6, 7].

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Acknowledgements

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Bone Marrow Failure Research Program—Idea Development Award under Award No. W81XWH-18-1-0265 to YL. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This work was also supported in part by two NIH R56 Awards (R56DK119524-01 and R56AG05250), a DoD Career Development Award W81XWH-13-1-0187, a Scholar Award from the St. Baldrick’s Foundation, an Elsa Pardee Foundation New Investigator Award, a Leukemia Research Foundation New Investigator Award, a Showalter Trust Fund New Investigator Award, an Alex Lemonade Stand Foundation grant, a Children’s Leukemia Research Association grant, and an American Cancer Society Institutional Research Grant to YL. SCN was supported by a NIH F32 Award 1F32CA203049-01.The authors would like to acknowledge the Flow Cytometry Core and In vivo Therapeutic Core Laboratories, which were sponsored, in part, by the NIDDK Cooperative Center of Excellence in Hematology (CCEH) grant U54 DK106846. This work was supported, in part, by a Project Development Team within the ICTSI NIH/NCRR Grant Number UL1TR001108. We would like to thank Dr. Yang Xu at USCD for providing the p53R248W mice to the study.

Author contributions

SCN and YL designed the research. SCN, SC, RG, CY, MK, SV, ACF, CW, and CD performed the research. SCN, SC, and YL analyzed the data and performed the statistical analysis. GES performed pathological analysis. HSB, LDM, and RK provided reagents and constructive advice to the study. SCN, SC, and YL wrote the paper. All authors read, commented on, and approved the paper.

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Authors and Affiliations

  1. Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Sarah C. Nabinger, Rui Gao, Chonghua Yao, Michihiro Kobayashi, Sasidhar Vemula, Aidan C. Fahey, Christine Wang, Cecil Daniels, Lindsey D. Mayo, Reuben Kapur & Yan Liu

  2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Sisi Chen & Yan Liu

  3. Department of Rheumatism, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Chonghua Yao

  4. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    H. Scott Boswell

  5. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    George E. Sandusky

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Correspondence to Yan Liu.

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Nabinger, S.C., Chen, S., Gao, R. et al. Mutant p53 enhances leukemia-initiating cell self-renewal to promote leukemia development. Leukemia 33, 1535–1539 (2019). https://doi.org/10.1038/s41375-019-0377-0

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