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XBP1 Promotes NRAS Pre-B Acute Lymphoblastic Leukaemia Through IL-7 Receptor Signalling and Provides a Therapeutic Vulnerability for Oncogenic RAS

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Journal J Cell Mol Med
Date 2023 Sep 27
PMID 37753803
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Abstract

Activating point mutations of the RAS gene act as driver mutations for a subset of precursor-B cell acute lymphoblastic leukaemias (pre-B ALL) and represent an ambitious target for therapeutic approaches. The X box-binding protein 1 (XBP1), a key regulator of the unfolded protein response (UPR), is critical for pre-B ALL cell survival, and high expression of XBP1 confers poor prognosis in ALL patients. However, the mechanism of XBP1 activation has not yet been elucidated in RAS mutated pre-B ALL. Here, we demonstrate that XBP1 acts as a downstream linchpin of the IL-7 receptor signalling pathway and that pharmacological inhibition or genetic ablation of XBP1 selectively abrogates IL-7 receptor signalling via inhibition of its downstream effectors, JAK1 and STAT5. We show that XBP1 supports malignant cell growth of pre-B NRAS ALL cells and that genetic loss of XBP1 consequently leads to cell cycle arrest and apoptosis. Our findings reveal that active XBP1 prevents the cytotoxic effects of a dual PI3K/mTOR pathway inhibitor (BEZ235) in pre-B NRAS ALL cells. This implies targeting XBP1 in combination with BEZ235 as a promising new targeted strategy against the oncogenic RAS in NRAS -mutated pre-B ALL.

Citing Articles

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PMID: 38928295 PMC: 11203805. DOI: 10.3390/ijms25126589.


XBP1 promotes NRAS pre-B acute lymphoblastic leukaemia through IL-7 receptor signalling and provides a therapeutic vulnerability for oncogenic RAS.

Salimi A, Schemionek-Reinders M, Huber M, Vieri M, Patterson J, Alten J J Cell Mol Med. 2023; 27(21):3363-3377.

PMID: 37753803 PMC: 10623536. DOI: 10.1111/jcmm.17904.

References
1.
Ouyang W, Beckett O, Flavell R, Li M . An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity. 2009; 30(3):358-71. PMC: 2692529. DOI: 10.1016/j.immuni.2009.02.003. View

2.
Ojha R, Amaravadi R . Targeting the unfolded protein response in cancer. Pharmacol Res. 2017; 120:258-266. PMC: 5542584. DOI: 10.1016/j.phrs.2017.04.003. View

3.
Kerdiles Y, Beisner D, Tinoco R, Dejean A, Castrillon D, DePinho R . Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol. 2009; 10(2):176-84. PMC: 2856471. DOI: 10.1038/ni.1689. View

4.
Sanchez V, Nichols C, Kim H, Gang E, Kim Y . Targeting PI3K Signaling in Acute Lymphoblastic Leukemia. Int J Mol Sci. 2019; 20(2). PMC: 6358886. DOI: 10.3390/ijms20020412. View

5.
Ribeiro D, Melao A, van Boxtel R, Santos C, Silva A, Silva M . STAT5 is essential for IL-7-mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells. Blood Adv. 2018; 2(17):2199-2213. PMC: 6134214. DOI: 10.1182/bloodadvances.2018021063. View