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RNA helicase DHX15 exemplifies a unique dependency in acute leukemia

Hao Guo, Jin Xu, Peiqi Xing, Qilong Li, Donghai Wang, Chao Tang, Bruno Palhais (UGent) , Juliette Roels (UGent) , Jiaxu Liu, Sa Pan, et al.
(2023) HAEMATOLOGICA. 108(8). p.2029-2043
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Abstract
RNA-binding proteins (RBPs) have emerged as essential regulators to control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. Yet implications of essential RBPs during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBPs identifies RNA helicase DHX15, which facilitates the disassembly of spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during CD4-CD8-(DN)-to-CD4+CD8+(DP) transition. Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate prominent anti-T-ALL efficacy. Collectively, we here highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach that splicing perturbation by targeting spliceosome disassembly may achieve considerable anti-tumor efficacy.
Keywords
Hematology

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MLA
Guo, Hao, et al. “RNA Helicase DHX15 Exemplifies a Unique Dependency in Acute Leukemia.” HAEMATOLOGICA, vol. 108, no. 8, Ferrata Storti Foundation (Haematologica), 2023, pp. 2029–43, doi:10.3324/haematol.2022.282066.
APA
Guo, H., Xu, J., Xing, P., Li, Q., Wang, D., Tang, C., … Liu, H. (2023). RNA helicase DHX15 exemplifies a unique dependency in acute leukemia. HAEMATOLOGICA, 108(8), 2029–2043. https://doi.org/10.3324/haematol.2022.282066
Chicago author-date
Guo, Hao, Jin Xu, Peiqi Xing, Qilong Li, Donghai Wang, Chao Tang, Bruno Palhais, et al. 2023. “RNA Helicase DHX15 Exemplifies a Unique Dependency in Acute Leukemia.” HAEMATOLOGICA 108 (8): 2029–43. https://doi.org/10.3324/haematol.2022.282066.
Chicago author-date (all authors)
Guo, Hao, Jin Xu, Peiqi Xing, Qilong Li, Donghai Wang, Chao Tang, Bruno Palhais, Juliette Roels, Jiaxu Liu, Sa Pan, Jinyan Huang, Zhaoqi Liu, Ping Zhu, Tom Taghon, Guoliang Qing, Pieter Van Vlierberghe, and Hudan Liu. 2023. “RNA Helicase DHX15 Exemplifies a Unique Dependency in Acute Leukemia.” HAEMATOLOGICA 108 (8): 2029–2043. doi:10.3324/haematol.2022.282066.
Vancouver
1.
Guo H, Xu J, Xing P, Li Q, Wang D, Tang C, et al. RNA helicase DHX15 exemplifies a unique dependency in acute leukemia. HAEMATOLOGICA. 2023;108(8):2029–43.
IEEE
[1]
H. Guo et al., “RNA helicase DHX15 exemplifies a unique dependency in acute leukemia,” HAEMATOLOGICA, vol. 108, no. 8, pp. 2029–2043, 2023.
@article{01GYYXDXXVJJ6YQS32ZET8PCXY,
  abstract     = {{RNA-binding proteins (RBPs) have emerged as essential regulators to control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. Yet implications of essential RBPs during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBPs identifies RNA helicase DHX15, which facilitates the disassembly of spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during CD4-CD8-(DN)-to-CD4+CD8+(DP) transition. Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate prominent anti-T-ALL efficacy. Collectively, we here highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach that splicing perturbation by targeting spliceosome disassembly may achieve considerable anti-tumor efficacy.}},
  author       = {{Guo, Hao and Xu, Jin and Xing, Peiqi and Li, Qilong and Wang, Donghai and Tang, Chao and Palhais, Bruno and Roels, Juliette and Liu, Jiaxu and Pan, Sa and Huang, Jinyan and Liu, Zhaoqi and Zhu, Ping and Taghon, Tom and Qing, Guoliang and Van Vlierberghe, Pieter and Liu, Hudan}},
  issn         = {{0390-6078}},
  journal      = {{HAEMATOLOGICA}},
  keywords     = {{Hematology}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{2029--2043}},
  publisher    = {{Ferrata Storti Foundation (Haematologica)}},
  title        = {{RNA helicase DHX15 exemplifies a unique dependency in acute leukemia}},
  url          = {{http://doi.org/10.3324/haematol.2022.282066}},
  volume       = {{108}},
  year         = {{2023}},
}
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