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Acute lymphoblastic leukemia

Inactivation of KLF4 promotes T-cell acute lymphoblastic leukemia and activates the MAP2K7 pathway

Leukemia volume 31, pages 1314–1324 (2017)Cite this article

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a high incidence of relapse in pediatric ALL. Although most T-ALL patients exhibit activating mutations in NOTCH1, the cooperating genetic events required to accelerate the onset of leukemia and worsen disease progression are largely unknown. Here, we show that the gene encoding the transcription factor KLF4 is inactivated by DNA methylation in children with T-ALL. In mice, loss of KLF4 accelerated the development of NOTCH1-induced T-ALL by enhancing the G1-to-S transition in leukemic cells and promoting the expansion of leukemia-initiating cells. Mechanistically, KLF4 represses the gene encoding the kinase MAP2K7. Our results showed that in murine and pediatric T-ALL, loss of KLF4 leads to aberrant activation of MAP2K7 and of the downstream effectors JNK and ATF2. As a proof-of-concept for the development of a targeted therapy, administration of JNK inhibitors reduced the expansion of leukemia cells in cell-based and patient-derived xenograft models. Collectively, these data uncover a novel function for KLF4 in regulating the MAP2K7 pathway in T-ALL cells, which can be targeted to eradicate leukemia-initiating cells in T-ALL patients.

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Acknowledgements

We thank A Ferrando (Columbia University) for providing the T-ALL cell lines, W Pear (University of Pennsylvania) for supplying the retroviral constructs, A. Major for immunohistochemical analysis, P Labhart (Active Motif) for the bioinformatic analysis of KLF4 gene methylation and genome-wide binding, and Karen Prince for the preparation of figures. This work was supported by the Rally Foundation for Childhood Cancer Research (to HDL), the Gabrielle’s Angel Foundation for Cancer Research (to HDL), the Cancer Prevention Research Institute of Texas (to HDL), and the Cytometry and Cell Sorting Core at Baylor College of Medicine for their assistance (P30 AI036211, P30 CA125123, and S10 RR024574). The GEO accession numbers for gene expression data and ChIP-seq data are GSE75663 and GSE76474, respectively.

Author contributions

YS designed and performed most of the experiments, interpreted the data, and wrote the manuscript. CSP and KS carried out the initial studies in the Notch1-induced T-ALL mouse model. MP generated the different mouse models used in this study. TH and KR provided pediatric patient samples and commented on the work. TAM performed bioinformatic analyses. NG provided JNK inhibitors. JM analyzed gene expression in pediatric patients with T-ALL. HDL conceived of the project, designed and interpreted the experiments, directed the project as the principal investigator, wrote the manuscript, and funded the research.

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Author notes

  1. K Suppipat

    Present address: 7Present address: Center of Excellence for Cell and Stem Cell Therapy, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand.,

  2. C S Park and K Suppipat: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA

    Y Shen, C S Park, T-A Mistretta, M Puppi & H D Lacorazza

  2. Texas Children’s Cancer and Hematology Center, Houston, TX, USA

    K Suppipat, T M Horton & K Rabin

  3. Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

    T M Horton, K Rabin & H D Lacorazza

  4. Department of Cancer Biology, Department of Biological Chemistry and Molecular Pharmacology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    N S Gray

  5. Department of Pediatric Oncology/Hematology, Erasmus Medical Center/Sophia Children’s Hospital, Rotterdam and the Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    J P P Meijerink

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  1. Y Shen
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Shen, Y., Park, C., Suppipat, K. et al. Inactivation of KLF4 promotes T-cell acute lymphoblastic leukemia and activates the MAP2K7 pathway. Leukemia 31, 1314–1324 (2017). https://doi.org/10.1038/leu.2016.339

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