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

Nat Med. 2018 Aug;24(8):1157-1166. doi: 10.1038/s41591-018-0105-8. Epub 2018 Jul 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Gene Expression Regulation, Leukemic
  • HSP90 Heat-Shock Proteins / metabolism
  • Heat Shock Transcription Factors / genetics
  • Heat Shock Transcription Factors / metabolism
  • Heat-Shock Response
  • Hematopoiesis
  • Humans
  • Mice, Inbred C57BL
  • Oncogenes*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Stress, Physiological*


  • HSP90 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Receptors, Notch