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Acute Lymphoblastic Leukemia

Low CtBP2 expression is associated with a stem cell-like signature and adverse clinical outcome in childhood B-cell lymphoblastic leukemia

Leukemia volume 35, pages 2684–2687 (2021)Cite this article

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Precursor B-cell lymphoblastic leukemia (B-ALL) is predominantly a pediatric malignancy and is derived from B-cell progenitors. B-ALL leukemogenesis arises mainly via genetic events, and current B-ALL risk stratification schemes are primarily based on the presence and type of recurrent cytogenetic and genetic abnormalities. Refractory disease is not exclusively associated with any particular cytogenetic abnormality; poor outcome occurs in a subset of patients in all at-risk groups. Investigation of genetic events that may further define this refractory group is ongoing with limited results. Epigenetic factors may be considered as one of the pathogenic features driving refractory disease in B-ALL and are a focus of this report. In our previous studies on epigenomic profiling of B-ALLs, we discovered that binding sites of polycomb and COOH-termina-binding protein 2 (CtBP2) are important targets for de novo hypermethylation in most cases [1]. Through this epigenetic modulation, tumor cells may mimic the bivalent status of embryonic stem cells (ESCs) and escape from preprogrammed developmental fate to maintain pluripotency. Because the degrees of hypermethylation of polycomb- and CtBP2-binding sites varied among different tumors, we speculated that heterogeneity may exist in function and expression of these core regulators, with possible impacts on ALL pathophysiology. Therefore, we examined several core regulators in another cohort and found that CtBP2 expression is highly variable among B-ALL cases and may impact patients’ clinical outcome.

We analyzed a total of 199 cases with adequate specimen quality and high leukemic burden (>90%). Collectively, 82, 107, and 10 cases were classified into high, intermediate, and low CtBP2 expression, respectively. CtBP2 expression was not significantly associated with age, sex nor white blood cell (WBC) counts at initial diagnosis (Supplementary Table S2). Low CtBP2 expression was more frequently observed (~16.7%) in cases with ETV6/RUNX1 compared to other cytogenetics groups (0–3.4%; P = 0.013). Short-term cytomorphologic response at days 7 and 14 after induction therapy were also evaluated but there was no significant difference among the three CtBP2 groups.

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Fig. 1: Immunohistochemical stain patterns for CtBP2 in bone marrow biopsy of B-ALL cases.

References

  1. Lee ST, Muench MO, Fomin ME, Xiao J, Zhou M, de Smith A, et al. Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures. Nucleic Acids Res. 2015;43:2590–602.

    Article  CAS  Google Scholar 

  2. McFadden DG, Barbosa AC, Richardson JA, Schneider MD, Srivastava D, Olson EN. The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner. Development. 2005;132:189–201.

    Article  CAS  Google Scholar 

  3. Yan Y, Su M, Song Y, Tang Y, Tian XC, Rood D, et al. Tbx1 modulates endodermal and mesodermal differentiation from mouse induced pluripotent stem cells. Stem Cells Dev. 2014;23:1491–500.

    Article  CAS  Google Scholar 

  4. Boller S, Li R, Grosschedl R, Defining B. Cell chromatin: lessons from EBF1. Trends Genet. 2018;34:257–69.

    Article  CAS  Google Scholar 

  5. Zuccotti A, Le Magueresse C, Chen M, Neitz A, Monyer H. The transcription factor Fezf2 directs the differentiation of neural stem cells in the subventricular zone toward a cortical phenotype. Proc Natl Acad Sci USA. 2014;111:10726–31.

    Article  CAS  Google Scholar 

  6. Palmer NP, Schmid PR, Berger B, Kohane IS. A gene expression profile of stem cell pluripotentiality and differentiation is conserved across diverse solid and hematopoietic cancers. Genome Biol. 2012;13:R71.

    Article  Google Scholar 

  7. Turner J, Crossley M. The CtBP family: enigmatic and enzymatic transcriptional co-repressors. Bioessays. 2001;23:683–90.

    Article  CAS  Google Scholar 

  8. Kim TW, Kang BH, Jang H, Kwak S, Shin J, Kim H, et al. Ctbp2 modulates NuRD-mediated deacetylation of H3K27 and facilitates PRC2-mediated H3K27me3 in active embryonic stem cell genes during exit from pluripotency. Stem Cells. 2015;33:2442–55.

    Article  CAS  Google Scholar 

  9. Verger A, Perdomo J, Crossley M. CtBP and hematopoietic transcriptional regulators. Madame Curie Bioscience Database [Internet] 2000–2013. https://www.ncbi.nlm.nih.gov/books/NBK6187/.

  10. Byun JS, Gardner K. C-terminal binding protein: a molecular link between metabolic imbalance and epigenetic regulation in breast cancer. Int J Cell Biol. 2013;2013:647975.

    Article  Google Scholar 

  11. Chinnadurai G. CtBP, an unconventional transcriptional corepressor in development and oncogenesis. Mol Cell. 2002;9:213–24.

    Article  CAS  Google Scholar 

  12. Cui L, Gao C, Wang CJ, Liu SG, Wu MY, Zhang RD, et al. Low expression of CTBP2 and CASP8AP2 predicts risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a retrospective cohort study. Pediatr Hematol Oncol. 2020;37:732–46.

    Article  CAS  Google Scholar 

  13. Patani H, Rushton MD, Higham J, Teijeiro SA, Oxley D, Cutillas P, et al. Transition to naive human pluripotency mirrors pan-cancer DNA hypermethylation. Nat Commun. 2020;11:3671.

    Article  CAS  Google Scholar 

  14. Lee ST, Wiemels JL. Genome-wide CpG island methylation and intergenic demethylation propensities vary among different tumor sites. Nucleic Acids Res. 2016;44:1105–17.

    Article  CAS  Google Scholar 

  15. Wang Y, Che S, Cai G, He Y, Chen J, Xu W. Expression and prognostic significance of CTBP2 in human gliomas. Oncol Lett. 2016;12:2429–34.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Research Foundation of Korea (2016R1D1A1B01010566, 2018R1C1B5084962). California work was supported by research grants from the National Institutes of Health (R01CA155461 and P01ES018172) and the Environmental Protection Agency (RD83451101), United States.

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  1. These authors contributed equally: Sejong Chun, Hyun-Young Kim

Authors and Affiliations

  1. Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea

    Sejong Chun

  2. Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Hyun-Young Kim, Hee-Jin Kim & Sun-Hee Kim

  3. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Hong Hoe Koo & Keon Hee Yoo

  4. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA

    Mi Zhou & Joseph L. Wiemels

  5. Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    Seung-Tae Lee

  6. Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Joseph L. Wiemels

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Chun, S., Kim, HY., Kim, HJ. et al. Low CtBP2 expression is associated with a stem cell-like signature and adverse clinical outcome in childhood B-cell lymphoblastic leukemia. Leukemia 35, 2684–2687 (2021). https://doi.org/10.1038/s41375-021-01151-2

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