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

Abstract

Cellular transformation is accompanied by extensive re-wiring 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.

Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury

“…These data were consistent with a previous report that showed that Notch1 binds to the promoters of HSF1 to regulate the heat shock response pathway. 26 Moreover, further evidence revealed that the adoptive transfer of BMMs pretreated with lentivirus expressing HSF1 into Notch1 M-KO mice ameliorated IRinduced hepatocellular damage. Thus, HSF1 is crucial for Notch1 signaling-mediated immune regulation in response to IR stress.…”

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

“…More recently, it has been shown that HSF1 is abundant in the nuclei of mammary tumor cells in clinical biopsy samples, indicating constitutive activation of the heat shock response in cancer [38]. Perhaps most significantly, it has been shown that knockout of HSF1 in mouse tumor models, including p53-deficient or Her2-overexpressing spontaneous cancer, severely curtails tumor growth [13,[45][46][47][62][63][64]. These studies provide strong evidence for an important causal and essential role for the factor in tumorigenesis.…”

“…These studies provide strong evidence for an important causal and essential role for the factor in tumorigenesis. In addition, higher levels of HSF1 mRNA found in tumor biopsies from a wide range of disease types may indicate a role for the expression of the factor in tumor morbidity ( Figure 2A,B) [47,65]. However, only in the case of hepatic cancer did we find a significant correlation between elevated HSF1 gene expression and the survival of patients ( Figure 2F) compared to breast and ovarian cancer, in which we could detect no significant relationship ( Figure 2D,E).…”

“…An important advance gained from these studies was the revelation of the extent of HSF1 transcriptomic negative regulation, as well as a cohort of HSF1 targets in cancer cells distinct to that of heat shock [39,43]. The precise roles of HSF1 in the multiple pathophysiological changes underlying carcinogenesis and tumor progression are still emerging, although numerous studies indicate that HSF1 knockout is effective in inhibiting cancer formation in a range of tissues as shown by several experimental mouse tumor models [44][45][46][47]. Similarly, using data provided by the Cancer Dependency Map (DepMap) study, Dong et al illustrated the relative high importance of HSF1 to transformed cells compared to other major oncogenic factors [48,49].…”

NOTCH assembles a transcriptional repressive complex containing NuRD and PRC1 to repress genes involved in cell proliferation and differentiation

“…Gene expression analyses were first performed with microarray data. For genome-wide detection, we then integrated polyA+ RNAseq analysis from public dataset GSE90715 (Kourtis et al, 2018) using T-ALL cell line treated with DMSO or GSI for the same time (24 hrs). Gene expression levels in duplicates normalized by fpkm were directly recovered in DMSO and GSI conditions.…”