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

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

Author information

1
Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA. Nikolaos.Kourtis@nyumc.org.
2
Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA.
3
Molecular Biomedicine Program, CINVESTAV IPN, Mexico City, Mexico.
4
CONACYT-Centro de Investigacion Biomedica de Oriente, IMSS Delegacion Puebla, Atlixco, Mexico.
5
Haematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
6
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Centre (UMC), Utrecht, the Netherlands.
7
Program in Chemical Biology, Sloan Kettering Institute, New York, NY, USA.
8
Institute for Cancer Genetics, Department of Pathology and Department of Pediatrics, Columbia University, New York, NY, USA.
9
PsychoGenics Inc., Tarrytown, New York, NY, USA.
10
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
11
Montefiore Medical Center, New York, NY, USA.
12
Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY, USA.
13
Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA. Iannis.Aifantis@nyumc.org.

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.

PMID:
30038221
PMCID:
PMC6082694
DOI:
10.1038/s41591-018-0105-8
[Indexed for MEDLINE]
Free PMC Article

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