Abstract

Cellular transformation is accompanied by extensive rewiring of many biological processes leading to augmented levels of distinct types of cellular stress, including proteotoxic stress. Cancer cells critically depend on stress-relief pathways for their survival. However, the mechanisms underlying the transcriptional initiation and maintenance of the oncogenic stress response remain elusive. Here, we show that the expression of heat shock transcription factor 1 (HSF1) and the downstream mediators of the heat shock response is transcriptionally upregulated in T cell acute lymphoblastic leukemia (T-ALL). Hsf1 ablation suppresses the growth of human T-ALL and eradicates leukemia in mouse models of T-ALL, while sparing normal hematopoiesis. HSF1 drives a compact transcriptional program and among the direct HSF1 targets, specific chaperones and co-chaperones mediate its critical role in T-ALL. Notably, we demonstrate that the central T-ALL oncogene NOTCH1 hijacks the cellular stress response machinery by inducing the expression of HSF1 and its downstream effectors. The NOTCH1 signaling status controls the levels of chaperone/co-chaperone complexes and predicts the response of T-ALL patient samples to HSP90 inhibition. Our data demonstrate an integral crosstalk between mediators of oncogene and non-oncogene addiction and reveal critical nodes of the heat shock response pathway that can be targeted therapeutically.

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Acknowledgements

We thank all members of the Aifantis laboratory for discussions throughout the duration of this project; T. Papagiannakopoulos and P. Ntziachristos for critical assessment of this work; E. Christians (UPMC Univ. Paris 06, CNRS) for the Hsf1f/f mice; A. Heguy and the NYU Genome Technology Center (supported in part by National Institutes of Health (NIH)/National Cancer Institute (NCI) grant P30CA016087-30) for expertise with sequencing experiments; the NYU Histology Core (5P30CA16087-31) for assistance; C. Loomis and L. Chiriboga for immunohistochemistry experiments; C. Jamieson (UCSD) for human LICs; The ECOG-ACRIN Cancer Research Group for clinical specimens. This work has used computing resources at the High Performance Computing Facility at the NYU Medical Center. A.T. is supported by a Research Scholar Grant (RSG-15-189-01-RMC) from the American Cancer Society and a Leukemia & Lymphoma Society New Idea Award (8007-17). I.A. is supported by the NIH (R01CA133379, R01CA105129, R01CA149655, 5R01CA173636, 1R01CA194923), the NYSTEM program of the New York State Health Department (NYSTEM-N11G-255) and the Leukemia & Lymphoma Society (LLS) Translational Research Program (TRP). J.C.B. was supported by CONACyT​ (​​FOSISSS 2015-1-261848​)​ and​ ​IMSS​ (FIS/IMSS/PROT/G14/1289​). J.M. was supported by KWF BUIT2012-5358. N.K. is supported by a Human Frontiers Science Program (HFSP) Long Term Fellowship (LT000150/2013-L) and previously by a Charles H. Revson Senior Fellowship in Biomedical Science (15–31) and a European Molecular Biology Organization (EMBO) Long Term Fellowship (ALTF 850-2012).

Author information

Author notes

    • Jasper Mullenders

    Present address: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre (UMC), Utrecht, the Netherlands

    • Alberto Ambesi-Impiombato

    Present address: PsychoGenics Inc., Tarrytown, New York, NY, USA

  1. These authors contributed equally: Nikos Kourtis, Charalampos Lazaris.

Affiliations

  1. Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA

    • Nikos Kourtis
    • , Charalampos Lazaris
    • , Kathryn Hockemeyer
    • , Jasper Mullenders
    • , Yixiao Gong
    • , Thomas Trimarchi
    • , Kamala Bhatt
    • , Hai Hu
    • , Aristotelis Tsirigos
    •  & Iannis Aifantis
  2. Molecular Biomedicine Program, CINVESTAV IPN, Mexico City, Mexico

    • Juan Carlos Balandrán
  3. CONACYT–Centro de Investigacion Biomedica de Oriente, IMSS Delegacion Puebla, Atlixco, Mexico

    • Juan Carlos Balandrán
  4. Haematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    • Juan Carlos Balandrán
    • , Alejandra R. Jimenez
    •  & Monica L. Guzman
  5. Program in Chemical Biology, Sloan Kettering Institute, New York, NY, USA

    • Liza Shrestha
    •  & Gabriela Chiosis
  6. Institute for Cancer Genetics, Department of Pathology and Department of Pediatrics, Columbia University, New York, NY, USA

    • Alberto Ambesi-Impiombato
    •  & Adolfo A. Ferrando
  7. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    • Michelle Kelliher
  8. Montefiore Medical Center, New York, NY, USA

    • Elisabeth Paietta
  9. Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY, USA

    • Aristotelis Tsirigos

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Contributions

N.K. and I.A. designed the experiments and wrote the manuscript. N.K. performed most of the experiments. C.L. designed and performed bioinformatics analysis of genome-wide data. K.H., J.C.B, A.R.J., J.M. and T.T. performed experiments. Y.G. performed RNA-seq analysis. K.B. and H.H maintained the mouse colonies. L.S. provided molecular chaperones inhibitors. M.K. provided Tal1 cells. A.A.-I., E.P. and A.A.F. provided T-ALL patient expression data and patient samples. G.C. and M.L.G. provided molecular chaperones inhibitors and ideas. A.T. designed and performed bioinformatics analysis of genome-wide data and contributed ideas.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Nikos Kourtis or Iannis Aifantis.

Supplementary Information

  1. Supplementary Text and Figures

    Supplementary Figures 1–11 and Supplementary Tables 1 and 3

  2. Reporting Summary

  3. Supplementary Table 2

    Notch1-IC-interacting proteins in the mouse T-ALL 720 cell line or 293T cells

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https://doi.org/10.1038/s41591-018-0105-8