Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia

Nikos Kourtis, Charalampos Lazaris, Kathryn Hockemeyer, Juan Carlos Balandrán, Alejandra R. Jimenez, Jasper Mullenders, Yixiao Gong, Thomas Trimarchi, Kamala Bhatt, Hai Hu, Liza Shrestha, Alberto Ambesi-Impiombato, Michelle Kelliher, Elisabeth Paietta, Gabriela Chiosis, Monica L. Guzman, Adolfo A. Ferrando, Aristotelis Tsirigos, Iannis Aifantis

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1157-1166
Number of pages10
JournalNature Medicine
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2018

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kourtis, N., Lazaris, C., Hockemeyer, K., Balandrán, J. C., Jimenez, A. R., Mullenders, J., Gong, Y., Trimarchi, T., Bhatt, K., Hu, H., Shrestha, L., Ambesi-Impiombato, A., Kelliher, M., Paietta, E., Chiosis, G., Guzman, M. L., Ferrando, A. A., Tsirigos, A., & Aifantis, I. (2018). Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia. Nature Medicine, 24(8), 1157-1166. https://doi.org/10.1038/s41591-018-0105-8