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Acute lymphoblastic leukemia in children and SALL4 and BMI-1 gene expression

Pediatric Research volume 94, pages 1510–1515 (2023)Cite this article

Abstract

Background

Sal-like protein 4 transcription factor (SALL4) and B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) gene were reported to cause treatment failure and relapse in several malignancies. We aimed to evaluate the prognostic value of SALL4 and BMI-1 in children with acute lymphoblastic leukemia (ALL).

Methods

This prospective cohort study was carried out on 60 children with ALL as the patient group and 60 age- and sex-matched children as the control group. We evaluated the expression pattern of both SALL4 and BMI-1 genes in the peripheral blood using real-time reverse transcriptase-polymerase chain reaction in children with ALL at initial diagnosis before chemotherapy. We followed up with the patient group for 2 years for relapse or death.

Results

Both SALL4 and BMI-1 were overexpressed in ALL children compared to the control group. Moreover, the expression of SALL4 and BMI-1 in patients with relapse was significantly higher than those with complete remission. The best cut-off of SALL4 and BMI-1 to predict relapse were >2.21 and 0.55 yielding sensitivity of 92.3% and 84.6%, respectively. Patients with overexpression of SALL4 and BMI-1 had significantly shorter overall and disease-free survival.

Conclusions

SALL4 and BMI-1 could be useful prognostic markers in children with ALL to predict relapse.

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Fig. 1: Relative expression of SALL4 and BMI-1 among ALL patients and controls at initial diagnosis.
Fig. 2: Relative expression of SALL4 and BMI-1 among children with ALL with complete remission and those with relapse.
Fig. 3: Correlation between SALL4 with BMI-1 in ALL patients.
Fig. 4: ROC curves of SALL4 and BMI-1 genes to predict relapse among ALL patients.
Fig. 5: Kaplan-Meier curve in ALL patients with SALL4 expression gene.
Fig. 6: Kaplan-Meier curve in ALL patients with BMI-1 expression gene.

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References

  1. Gutierrez-Camino, A., Martin-Guerrero, I. & García-Orad, A. Genetic susceptibility in childhood acute lymphoblastic leukemia. Med. Oncol. 34, 179 (2017).

    Article  PubMed  Google Scholar 

  2. Antillón, F. G. et al. The treatment of childhood acute lymphoblastic leukemia in Guatemala: biologic features, treatment hurdles, and results. Cancer 123, 436–448 (2017).

    Article  PubMed  Google Scholar 

  3. Ferracin, M. & Micromarkers, N. M. An update on the role of microRNAs in cancer diagnosis and prognosis. Exp. Rev. Mol. Diagn. 15, 1369–1381 (2015).

    Article  CAS  Google Scholar 

  4. Azizi, Z., Rahgozar, S., Moafi, A., Dabaghi, M. & Nadimi, M. mRNA overexpression of BAALC: A novel prognostic factor for pediatric acute lymphoblastic leukemia. Biomed. Rep. 3, 371–374 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Szczepanek, J., Styczynski, J., Haus, O., Tretyn, A. & Wysocki, M. Relapse of acute lymphoblastic leukemia in children in the context of microarray analyses. Arch. Immunol. Ther. Exp. 59, 61–68 (2011).

    Article  CAS  Google Scholar 

  6. Bhojwani, D. & Pui, C. H. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 14, e205–e217 (2013).

    Article  PubMed  Google Scholar 

  7. Xiong, J. SALL4: engine of cell stemness. Curr. Gene Ther. 14, 400–411 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Zhang, X., Yuan, X., Zhu, W., Qian, H. & Xu, W. SALL4: an emerging cancer biomarker and target. Cancer Lett. 357, 55–62 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Yang, L. et al. The stem cell factor SALL4 is an essential transcriptional regulator in mixed lineage leukemia-rearranged leukemogenesis. J. Hematol. Oncol. 10, 159 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Liu, C. et al. SALL4 suppresses PTEN expression to promote glioma cell proliferation via PI3K/AKT signaling pathway. J. Neurooncol. 135, 1–10 (2017).

    Article  CAS  Google Scholar 

  11. Ma, Y. et al. SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood 108, 2726–2735 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ma, J. C. et al. Aberrant hypomethylation of SALL4 gene is associated with intermediate and poor karyotypes in acute myeloid leukemia. Clin. Biochem. 46, 304–307 (2013).

    Article  PubMed  Google Scholar 

  13. Kohlhase, J. et al. Okihiro syndrome is caused by SALL4 mutations. Hum. Mol. Genet. 11, 2979–2987 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Deloukas, P. et al. The DNA sequence and comparative analysis of human chromosome 20. Nature 414, 865–871 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Ueno, S. et al. Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: mechanism, function, and implication for a potential novel therapeutic target. Exp. Hematol. 42, 307–316 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Haupt, Y., Alexander, W. S., Barri, G., Klinken, S. P. & Adams, J. M. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in Eμ-myc transgenic mice. Cell 65, 753–763 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. van Lohuizen, M. et al. Identification of cooperating oncogenes in Eμ-myc transgenic mice by provirus tagging. Cell 65, 737–752 (1991).

    Article  PubMed  Google Scholar 

  18. Berger, R., Baranger, L., Bernheim, A., Valensi, F. & Flandrin, G. Cytogenetics of T-cell malignant lymphoma. Report of 17 cases and review of the chromosomal breakpoints. Cancer Genet. Cytogenet. 36, 123–130 (1988).

    Article  CAS  PubMed  Google Scholar 

  19. Alkema, M. J., Wiegant, J., Raap, A. K., Berns, A. & van Lohuizen, M. Characterization and chromosomal localization of the human proto-oncogene BMI-1. Hum. Mol. Genet. 2, 1597–1603 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Pui, C. H. et al. An analysis of leukemic cell chromosomal features in infants. Blood 69, 1289–1293 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Park, I. K. et al. BMI-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Lessard, J. & Sauvageau, G. BMI-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Molofsky, A. V. et al. BMI-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Facchino, S., Abdouh, M., Chatoo, W. & Bernier, G. BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J. Neurosci. 30, 10096–10111 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ismail, I. H., Andrin, C., McDonald, D. & Hendzel, M. J. BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J. Cell Biol. 191, 45–60 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bruggeman, S. W. et al. BMI-1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12, 328–341 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Yong, A. S. et al. Improved outcome following allogeneic stem cell transplantation in chronic myeloid leukemia is associated with higher expression of BMI-1 and immune responses to BMI-1 protein. Leukemia 25, 629–637 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mohty, M. et al. Association between BMI-1 expression, acute graft-versus-host disease, and outcome following allogeneic stem cell transplantation from HLA-identical siblings in chronic myeloid leukemia. Blood 112, 2163–2166 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. van Galen, J. C. et al. Expression of the polycomb-group gene BMI1 is related to an unfavourable prognosis in primary nodal DLBCL. J. Clin. Pathol. 60, 167–172 (2007).

    Article  PubMed  Google Scholar 

  30. Yang, J. C. et al. BMI-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc. Natl Acad. Sci. USA 104, 10494–10499 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. PUI, C. H. et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N. Engl. J. Med. 360, 2730–2741 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lanzkowsky, P. in Manual of Pediatric Hematology and Oncology 6th edn, Ch. 18 (ed. Lanzkowsky, P.) 367–387 (Academic Press, 2016).

  33. Woo, J. S., Alberti, M. O. & Tirado, C. A. Childhood B-acute lymphoblastic leukemia: a genetic update. Exp. Hematol. Oncol. 3, 16 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pui, C. H., Robison, L. L. & Look, A. T. Acute lymphoblastic leukaemia. Lancet 371, 1030–1043 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Ohadi, F., Rahgozar, S. & Ghodousi, E. Sal-like protein 4 transcription factor: a significant diagnostic biomarker involved in childhood ALL resistance and relapse. Cancer Manag. Res. 12, 1611–1619 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gao, C., Kong, N. R. & Chai, L. The role of stem cell factor SALL4 in leukemogenesis. Crit. Rev. Oncog. 16, 1–2 (2011).

    Article  Google Scholar 

  37. Peng, H. et al. Upregulation of the proto-oncogene BMI-1 predicts a poor prognosis in pediatric acute lymphoblastic leukemia. BMC Cancer 17, 76 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Shen, Q. et al. The differential expression pattern of the BMI-1, SALL4 and ABCA3 genes in myeloid leukemia. Cancer Cell Int. 12, 42 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cui, W. et al. Differential expression of the novel oncogene, SALL4, in lymphoma, plasma cell myeloma, and acute lymphoblastic leukemia. Mod. Pathol. 19, 1585–1592 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Tang, P., Sun, H., Liu, Y., Wang, G. & Yin, Y. Expression of SALL4 and BMI-1 mRNA in acute leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 16, 1271–1274 (2008).

    CAS  PubMed  Google Scholar 

  41. Li, W. et al. Overcoming ABC transporter-mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies. Drug Resist. Updat. 27, 14–29 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Jeong, H. W. et al. SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes. PLoS ONE 6, e18372 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mihara, K. et al. BMI-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis. Blood 107, 305–308 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the nurses at Clinical Pathology and Pediatric Department, Tanta University Hospital for their assistance in conducting the study. Also, we thank Mr. Amgad Hamza for his assistance in statistical analysis.

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Authors and Affiliations

  1. Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Hossam Hodeib, Amira Youssef & Dina Abdelhai

  2. Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Doaa El Amrousy, Hassan Al-Asy, Ahmed Shabana & Shimaa Elnemr

  3. Clinical Oncology Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Rasha Khedr

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  1. Hossam Hodeib
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Contributions

D.E.A.: acquisition of data, recruitment of patients, drafting, and final approval of the manuscript. H.H.: idea of the research, performing the statistical analysis, performing laboratory analysis, drafting, and final approval of the manuscript. A.Y.: acquisition of data, performing laboratory analysis, drafting. and final approval of the manuscript. R.K.: acquisition of data, recruitment of patients, drafting, and final approval of the manuscript. H.A.-A.: acquisition of data, statistical analysis, drafting, and final approval of the manuscript. A.S.: acquisition of data, help in the statistical analysis, drafting, and final approval of the manuscript. S.E.: help in the statistical analysis, drafting, and final approval of the manuscript. D.A.: acquisition of data, performing laboratory analysis, drafting, and final approval of the manuscript.

Corresponding author

Correspondence to Doaa El Amrousy.

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The authors declare no competing interests.

IRB approval

The study was approved by the local ethics committee of the Faculty of Medicine, Tanta University, Egypt.

Patient consent

The patients were enrolled after obtaining written informed consent from their parents.

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Hodeib, H., El Amrousy, D., Youssef, A. et al. Acute lymphoblastic leukemia in children and SALL4 and BMI-1 gene expression. Pediatr Res 94, 1510–1515 (2023). https://doi.org/10.1038/s41390-021-01854-3

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  • DOI: https://doi.org/10.1038/s41390-021-01854-3

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