WGCNA-based identification of anoikis-related subtypes, prognostic significance, and characterisation of the immune microenvironment in Philadelphia-negative acute lymphoblastic leukaemia

  • Na Li Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou 215000, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215000, China
  • Yang Hong Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou 215000, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215000, China
  • Ling Zhang Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou 215000, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215000, China
  • Aining Sun Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou 215000, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215000, China
Keywords: ph-neg B-ALL; anoikis; WGCNA; immunmicroenvironment
Article ID: 90

Abstract

The clinical outcomes and incidence of Philadelphia chromosome-negative B cell acute lymphoblastic leukaemia (ph-neg B-ALL) vary significantly across different age groups, influencing the prognosis. Despite recent advancements in diagnostic and therapeutic techniques, the detailed prognosis for ph-negative B-ALL across age demographics remains to be elucidated. In this study, clinical data were obtained from 80 patients with ph-neg B-ALL who were diagnosed at our centre. Ribonucleic acid sequencing was performed using their initial bone marrow aspirate samples. By employing weighted gene co-expression network analysis (WGCNA) on 408 anoikis-related genes (ARGs), four different modules were identified and subsequently analysed through bioinformatics. The WGCNA revealed distinct co-expression modules among ARGs. Specifically, the ARGs in the turquoise module might assess the risk associated with newly diagnosed ph-neg B-ALL. Additionally, the study revealed significant heterogeneity in the immune microenvironment and genome variance, highlighting the notable heterogeneity within the disease. 408 ARGs were screened out and four different co-expression modules were constructed by WGCNA algorithms from the RNA-sequencing data of 80 ph-neg B-ALL patients; The ARGs in the turquoise module were the most, and it can be used to divide the de novo ph-neg B-ALL patients to different risk groups(high-risk and low-risk); The ph-neg B-ALL patients can be divided into PS-1 and PS-2, there is heterogeneity of genomes between PS-1 and PS-2; Immune infiltration difference exists in between PS-1 and PS-2. In conclusion, our study holds significant value in exploring the molecular pathways and mechanisms associated with anoikis implicated in ph-neg B-ALL, and in facilitating the development of treatments and prognostic tools for this disease

References

1. Abou Dalle I, Jabbour E, Short NJ, et al. Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Current Treatment Options in Oncology. 2019; 20(1). doi: 10.1007/s11864-019-0603-z

2. Burmeister T, Schwartz S, Bartram CR, et al. Patients’ age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group. Blood. 2008; 112(3): 918-919. doi: 10.1182/blood-2008-04-149286

3. Jabbour E, Richard-Carpentier G, Sasaki Y, et al. Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial. Lancet Haematol. 2020; 7(7): 523-533.doi:10.1016/s2352-3026(20)30144-7

4. Parikh SA, Litzow MR. Philadelphia chromosome-negative acute lymphoblastic leukemia: therapies under development. Future Oncology. 2014; 10(14): 2201-2212. doi: 10.2217/fon.14.81

5. Hong M, Clubb JD, Chen YY. Engineering CAR-T Cells for Next-Generation Cancer Therapy. Cancer Cell. 2020; 38(4): 473-488. doi: 10.1016/j.ccell.2020.07.005

6. Adeshakin FO, Adeshakin AO, Afolabi LO, et al. Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming. Frontiers in Oncology. 2021; 11. doi: 10.3389/fonc.2021.626577

7. Kim YN, Koo KH, Sung JY, et al. Anoikis Resistance: An Essential Prerequisite for Tumor Metastasis. International Journal of Cell Biology. 2012; 2012: 1-11. doi: 10.1155/2012/306879

8. Frisch S, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. The Journal of cell biology. 1994; 124(4): 619-626. doi: 10.1083/jcb.124.4.619

9. Frisch SM, Ruoslahti K. Integrins and anoikis. Current Opinion in Cell Biology. 1997; 9(5): 701-706. doi: https://doi.org/10.1016/S0955-0674(97)80124-X

10. Han H jun, Sung JY, Kim SH, et al. Fibronectin regulates anoikis resistance via cell aggregate formation. Cancer Letters. 2021; 508: 59-72. doi: 10.1016/j.canlet.2021.03.011

11. Amoedo ND, Rodrigues MF, Rumjanek FD. MITOCHONDRIA: Are mitochondria accessory to metastasis? The International Journal of Biochemistry & Cell Biology. 2014; 51: 53-57. doi: 10.1016/j.biocel.2014.03.009

12. Zhong X, Rescorla FJ. Cell surface adhesion molecules and adhesion-initiated signaling: Understanding of anoikis resistance mechanisms and therapeutic opportunities. Cellular Signalling. 2012; 24(2): 393-401. doi: 10.1016/j.cellsig.2011.10.005

13. Kakavandi E, Shahbahrami R, Goudarzi H, et al. Anoikis resistance and oncoviruses. Journal of Cellular Biochemistry. 2017; 119(3): 2484-2491. doi: 10.1002/jcb.26363

14. Di Micco R, Krizhanovsky V, Baker D, et al. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature Reviews Molecular Cell Biology. 2020; 22(2): 75-95. doi: 10.1038/s41580-020-00314-w

15. Yu S, Li Y, Ren H, et al. PDK4 promotes tumorigenesis and cisplatin resistance in lung adenocarcinoma via transcriptional regulation of EPAS1. Cancer Chemotherapy and Pharmacology. 2020; 87(2): 207-215. doi: 10.1007/s00280-020-04188-9

16. Wong AW, Paulson QX, Hong J, et al. Alcohol promotes breast cancer cell invasion by regulating the Nm23-ITGA5 pathway. Journal of Experimental & Clinical Cancer Research. 2011; 30(1). doi: 10.1186/1756-9966-30-75

17. Gilmore AP. Anoikis. Cell Death & Differentiation. 2005; 12(S2): 1473-1477. doi: 10.1038/sj.cdd.4401723

18. Hong Y, Zhang L, Tian X, et al. Identification of immune subtypes of Ph-neg B-ALL with ferroptosis related genes and the potential implementation of Sorafenib. BMC Cancer. 2021; 21(1). doi: 10.1186/s12885-021-09076-w

19. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008; 9(1). doi: 10.1186/1471-2105-9-559

20. Karim MR, Beyan O, Zappa A, et al. Deep learning-based clustering approaches for bioinformatics. Briefings in Bioinformatics. 2020; 22(1): 393-415. doi: 10.1093/bib/bbz170

21. Dourthe ME, Rabian F, Yakouben K, et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia. 2021; 35(12): 3383-3393. doi: 10.1038/s41375-021-01281-7

22. Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nature Methods. 2015; 12(5): 453-457. doi: 10.1038/nmeth.3337

23. Yoshihara K, Shahmoradgoli M, Martínez E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nature Communications. 2013; 4(1). doi: 10.1038/ncomms3612

24. Rooney MS, Shukla SA, Wu CJ, et al. Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity. Cell. 2015; 160(1-2): 48-61. doi: 10.1016/j.cell.2014.12.033

25. Wu F, Li G, Liu H, et al. Molecular subtyping reveals immune alterations in IDH wild‐type lower‐grade diffuse glioma. The Journal of Pathology. 2020; 251(3): 272-283. doi: 10.1002/path.5468

26. Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade. Journal of Clinical Investigation. 2017; 127(8): 2930-2940. doi: 10.1172/jci91190

27. Lonial, Weiss, Usmani et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. The Lancet. 2016; 387(10027): 1551-1560. doi:10.1016/S0140-6736(15)01120-4

28. Chen L, Zhang YH, Wang S, et al. Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways. Liu B, ed. PLOS ONE. 2017; 12(9): e0184129. doi: 10.1371/journal.pone.0184129

29. Eckhardt CM, Madjarova SJ, Williams RJ, et al. Unsupervised machine learning methods and emerging applications in healthcare. Knee Surgery, Sports Traumatology, Arthroscopy. 2022; 31(2): 376-381. doi: 10.1007/s00167-022-07233-7

30. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences. 2005; 102(43): 15545-15550. doi: 10.1073/pnas.0506580102

31. Aldoss I, Yang D, Malki MMA, et al. Allogeneic Hematopoietic Cell Transplantation for Relapsed and Refractory Philadelphia Negative B Cell ALL in the Era of Novel Salvage Therapies. Transplantation and Cellular Therapy. 2021; 27(3): 255.e1-255.e9. doi: 10.1016/j.jtct.2020.12.020

32. Sattari Fard F, Jalilzadeh N, Mehdizadeh A, et al. Understanding and targeting anoikis in metastasis for cancer therapies. Cell Biology International. 2022; 47(4): 683-698. doi: 10.1002/cbin.11970

33. Qu J, Luo M, Zhang J, et al. A paradoxical role for sestrin 2 protein in tumor suppression and tumorigenesis. Cancer Cell International. 2021; 21(1). doi: 10.1186/s12935-021-02317-9

34. Korashy HM, Rahman AFMM, Kassem MG. Dasatinib. Profiles of Drug Substances, Excipients and Related Methodology. Published online 2014: 205-237. doi: 10.1016/b978-0-12-800173-8.00004-0

35. van Dijk EL, Jaszczyszyn Y, Naquin D, et al. The Third Revolution in Sequencing Technology. Trends in Genetics. 2018; 34(9): 666-681. doi: 10.1016/j.tig.2018.05.008

36. Khan SU, Fatima K, Malik F. Understanding the cell survival mechanism of anoikis-resistant cancer cells during different steps of metastasis. Clinical & Experimental Metastasis. 2022; 39(5): 715-726. doi: 10.1007/s10585-022-10172-9

37. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cellular & Molecular Immunology. 2020; 17(8): 807-821. doi: 10.1038/s41423-020-0488-6

38. Serafim Junior V, Fernandes GM de M, Oliveira-Cucolo JG de, et al. Role of Tropomyosin-related kinase B receptor and brain-derived neurotrophic factor in cancer. Cytokine. 2020; 136: 155270. doi: 10.1016/j.cyto.2020.155270

39. Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annual Review of Pathology: Mechanisms of Disease. 2021; 16(1): 223-249. doi: 10.1146/annurev-pathol-042020-042741

40. Chen LY, Kang LQ, Zhou HX, et al. Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia. Translational Oncology. 2020; 13(11): 100838. doi: 10.1016/j.tranon.2020.100838

41. Sun Z, Zhao Y, Wei Y, et al. Identification and validation of an anoikis-associated gene signature to predict clinical character, stemness, IDH mutation, and immune filtration in glioblastoma. Frontiers in Immunology. 2022; 13. doi: 10.3389/fimmu.2022.939523

42. Ye G, Yang Q, Lei X, et al. Nuclear MYH9-induced CTNNB1 transcription, targeted by staurosporin, promotes gastric cancer cell anoikis resistance and metastasis. Theranostics. 2020; 10(17): 7545-7560. doi: 10.7150/thno.46001

Published
2024-05-20
How to Cite
Li, N., Hong, Y., Zhang, L., & Sun, A. (2024). WGCNA-based identification of anoikis-related subtypes, prognostic significance, and characterisation of the immune microenvironment in Philadelphia-negative acute lymphoblastic leukaemia. Molecular & Cellular Biomechanics, 21, 90. https://doi.org/10.62617/mcb.v21.90
Section
Article