Integrative Alternative Splicing Analysis Reveals New Prognosis Signature in B-cell Acute Lymphoblastic Leukemia

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2024 Sep 9

PMID 39247833

Authors

Zhiyi Zhuo

Junfei Wang

Yonglei Zhang

Guoyu Meng

Affiliations

Soon will be listed here.

Abstract

The dysregulation of alternative splicing (AS) is increasingly recognized as a pivotal player in the pathogenesis, progression, and treatment resistance of B-cell acute lymphoblastic leukemia (B-ALL). Despite its significance, the clinical implications of AS events in B-ALL remain largely unexplored. This study developed a prognostic model based on 18 AS events (18-AS), derived from a meticulous integration of bioinformatics methodologies and advanced machine learning algorithms. The 18-AS signature observed in B-ALL distinctly categorized patients into different groups with significant differences in immune infiltration, V(D)J rearrangement, drug sensitivity, and immunotherapy outcomes. Patients classified within the high 18-AS group exhibited lower immune infiltration scores, poorer chemo- and immune-therapy responses, and worse overall survival, underscoring the model's potential in refining therapeutic strategies. To validate the clinical applicability of the 18-AS, we established an SF-AS regulatory network and identified candidate drugs. More importantly, we conducted in vitro cell proliferation assays to confirm our analysis, demonstrating that the High-18AS cell line (SUP-B15) exhibited significantly enhanced sensitivity to Dasatinib, Dovitinib, and Midostaurin compared to the Low-18AS cell line (REH). These findings reveal AS events as novel prognostic biomarkers and therapeutic targets, advancing personalized treatment strategies in B-ALL management.

References

Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F, Kojima S, Ueno T . Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nat Genet. 2016; 48(5):569-74. DOI: 10.1038/ng.3535. View

Shugay M, Bagaev D, Turchaninova M, Bolotin D, Britanova O, Putintseva E . VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires. PLoS Comput Biol. 2015; 11(11):e1004503. PMC: 4659587. DOI: 10.1371/journal.pcbi.1004503. View

Black K, Naqvi A, Asnani M, Hayer K, Yang S, Gillespie E . Aberrant splicing in B-cell acute lymphoblastic leukemia. Nucleic Acids Res. 2018; 46(21):11357-11369. PMC: 6277088. DOI: 10.1093/nar/gky946. View

Schwerk C, Prasad J, Degenhardt K, Erdjument-Bromage H, White E, Tempst P . ASAP, a novel protein complex involved in RNA processing and apoptosis. Mol Cell Biol. 2003; 23(8):2981-90. PMC: 152566. DOI: 10.1128/MCB.23.8.2981-2990.2003. View

Alexandrov L, Nik-Zainal S, Wedge D, Aparicio S, Behjati S, Biankin A . Signatures of mutational processes in human cancer. Nature. 2013; 500(7463):415-21. PMC: 3776390. DOI: 10.1038/nature12477. View

Levavasseur F, Oussous S, Zubaidan T, Kosmider O, Pendino F, Rombaut D . FOXP1 regulates oxidative stress, SIRT1 expression, and resistance to chemotherapies in acute myeloid leukemia cells. Blood Adv. 2023; 7(13):3265-3275. PMC: 10336262. DOI: 10.1182/bloodadvances.2022008585. View

Sotillo E, Barrett D, Black K, Bagashev A, Oldridge D, Wu G . Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015; 5(12):1282-95. PMC: 4670800. DOI: 10.1158/2159-8290.CD-15-1020. View

Meyer J, Wang J, Hogan L, Yang J, Dandekar S, Patel J . Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet. 2013; 45(3):290-4. PMC: 3681285. DOI: 10.1038/ng.2558. View

Pan Q, Shai O, Lee L, Frey B, Blencowe B . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008; 40(12):1413-5. DOI: 10.1038/ng.259. View

10.

Zheng S . Alternative splicing programming of axon formation. Wiley Interdiscip Rev RNA. 2020; 11(4):e1585. PMC: 7594648. DOI: 10.1002/wrna.1585. View

11.

Eucker J, Zang C, Zhou Y, Li X, Habbel P, Neumann C . The multi-tyrosine kinase inhibitor TKI258, alone or in combination with RAD001, is effective for treatment of human leukemia with BCR-ABL translocation in vitro. Anticancer Res. 2014; 34(9):4909-14. View

12.

Heltemes-Harris L, Hubbard G, LaRue R, Munro S, Yang R, Henzler C . Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia. Oncogene. 2021; 40(43):6166-6179. PMC: 8556320. DOI: 10.1038/s41388-021-02012-z. View

13.

Lilljebjorn H, Henningsson R, Hyrenius-Wittsten A, Olsson L, Orsmark-Pietras C, von Palffy S . Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia. Nat Commun. 2016; 7:11790. PMC: 4897744. DOI: 10.1038/ncomms11790. View

14.

Zhang X, Yin X, Zhang L, Ye Z, Liang G . Identification of drug targets and prognosis projection for uterine carcinosarcoma based on alternative splicing events. Comput Biol Med. 2022; 152:106346. DOI: 10.1016/j.compbiomed.2022.106346. View

15.

Papavasiliou F, Casellas R, Suh H, Qin X, Besmer E, Pelanda R . V(D)J recombination in mature B cells: a mechanism for altering antibody responses. Science. 1997; 278(5336):298-301. DOI: 10.1126/science.278.5336.298. View

16.

Nishimoto Y, Okano H . New insight into cancer therapeutics: induction of differentiation by regulating the Musashi/Numb/Notch pathway. Cell Res. 2010; 20(10):1083-5. DOI: 10.1038/cr.2010.122. View

17.

Wilkerson M, Hayes D . ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010; 26(12):1572-3. PMC: 2881355. DOI: 10.1093/bioinformatics/btq170. View

18.

Gajendran B, Varier K, Liu W, Wang C, Sample K, Zacksenhaus E . A C21-steroidal derivative suppresses T-cell lymphoma in mice by inhibiting SIRT3 via SAP18-SIN3. Commun Biol. 2020; 3(1):732. PMC: 7713351. DOI: 10.1038/s42003-020-01458-3. View

19.

Zhang M, Chen C, Lu Z, Cai Y, Li Y, Zhang F . Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms. Gastroenterology. 2023; 165(5):1151-1167. DOI: 10.1053/j.gastro.2023.07.019. View

20.

Acquaviva J, Chen X, Ren R . IRF-4 functions as a tumor suppressor in early B-cell development. Blood. 2008; 112(9):3798-806. PMC: 2572804. DOI: 10.1182/blood-2007-10-117838. View