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Significance of hematopoietic surface antigen CD34 in neuroblastoma prognosis and the genetic landscape of CD34-expressing neuroblastoma CSCs

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Abstract

High-risk neuroblastoma (HR-NB) is branded with hematogenous metastasis, relapses, and dismal long-term survival. Intensification of consolidation therapy with tandem/triple autologous stem cell (SC) rescue (with bone marrow [BM]/peripheral blood [PB] CD34+ selection) after myeloablative chemotherapy has improved long-term survival. However, the benefit is limited by the indication of NB cells in CD34+ PBSCs, CD34 expression in NB cells, and the risk of reinfusing NB cancer stem cells (NB CSCs) that could lead to post-transplant relapse. We investigated the association of CD34 surface expression (92 patients) with NB evolution/clinical outcomes. CD34 gene-level status in NB was assessed through RNA-Seq data mining (18 cohorts, n, 3324). Genetic landscape of CD34-expressing NB CSCs (CD133+CD34+) was compared with CD34− CSCs (CD133+CD34−). RNA-seq data revealed equivocal association patterns of CD34 expression with patient survival. Our immunohistochemistry data revealed definite, but rare (mean, 0.73%; range 0.00–7.87%; median, 0.20%) CD34 positivity in NB. CD34+ significantly associated with MYCN amplification (p, 0.003), advanced disease stage (p, 0.016), and progressive disease (PD, p < 0.0009) after clinical therapy. A general high-is-worse tendency was observed in patients with relapsed disease. High CD34+ correlated with poor survival in patients with N-MYC-amplified HR-NB. Gene expression analysis of CD34+-NB CSCs identified significant up (4631) and downmodulation (4678) of genes compared with NB CSCs that lack CD34. IPA recognized the modulation of crucial signaling elements (EMT, stemness maintenance, differentiation, inflammation, clonal expansion, drug resistance, metastasis) that orchestrate NB disease evolution in CD34+ CSCs compared with CD34− CSCs. While the function of CD34 in NB evolution requires further in-depth investigation, careful consideration should be exercised for autologous stem cell rescue with CD34+ selection in NB patients.

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Acknowledgments

The authors acknowledge the NB specimen providers: the Department of Pathology, University of Oklahoma Health Sciences Center; Cooperative Human Tissue Network (CHTN), which is funded by the National Cancer Institute (NCI), and; Oregon Health and Science University Biospecimen core. The authors acknowledge the Stephenson Cancer Center (SCC) Cancer Tissue pathology core for all TMA and IHC services and the SCC Cancer Functional Genomics core for help with whole genome gene expression. The authors also acknowledge the OUHSC Staff Editor (Ms. Kathy Kyler) for the help in critically reviewing this manuscript.

Funding

This work was financially supported by the National Institutes of Health, NIH-P20GM103639, and Oklahoma Center for the Advancement of Science and Technology, OCAST-HR19-04.

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Authors and Affiliations

  1. Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, BMSB 737, 940 Stanton L. Young Boulevard, Oklahoma City, OK, 73104, USA

    Natarajan Aravindan, Dinesh Babu Somasundaram & Terence S. Herman

  2. Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Natarajan Aravindan

  3. Department of Anesthesiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Natarajan Aravindan

  4. Stephenson Cancer Center, Oklahoma City, OK, 73104, USA

    Terence S. Herman & Sheeja Aravindan

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  1. Natarajan Aravindan
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The study was reviewed and approved by the Institutional Review Board at the University of Oklahoma Health Sciences Center (OUHSC), with permission for the research use of de-identified specimens. All experiments were performed in accordance with OUHSC IRB guidelines and regulations for the protection of human subjects.

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Highlights

• A small fraction of NB cells displays CD34 surface expression.

• Presence of CD34-expressing cells associated with advanced disease stage, N-MYC amplification, and disease evolution and, associated with the poor survival of high-risk patients with N-MYC amplification.

• Comparative gene expression profile of CD34+ NB CSCs recognized activated signaling pathways and cellular functions that correspond to disease evolution.

Electronic supplementary material

Figure S1

Association of CD34 transcription with NB disease evolution and poor clinical outcomes: (a) Box-whiskers plot with circles showing high levels of CD34 in high-risk aggressive metastatic stage 4 disease in a cohort of 161 patients. (b) Correlation of CD34 expression with NB clinical outcomes in a cohort of 283 patients. Kaplan-Meier curves showing decreased (b-i) overall survival (OS) and (b-ii) progression-free survival in patients with high CD34 expression compared with low CD34 expression. (c) Kaplan-Meier curve showing a pronounced decrease in relapse-free survival in N-MYC-non-amplified subset (n, 102) of NB patients with high CD34 expression. (d) Kaplan-Meier curves from an independent cohort of 88 NB patients showing significant decrease in (d-i) OS and (d-ii) relapse-free survival (RFS) with high levels of CD34 expression compared with patients who presented with low CD34. Within the same population, patients who presented with high-risk aggressive disease (INSS stage 4) displayed poor (d-iii) OS and (d- iv) RFS. (PPTX 560 kb)

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Aravindan, N., Somasundaram, D.B., Herman, T.S. et al. Significance of hematopoietic surface antigen CD34 in neuroblastoma prognosis and the genetic landscape of CD34-expressing neuroblastoma CSCs. Cell Biol Toxicol 37, 461–478 (2021). https://doi.org/10.1007/s10565-020-09557-x

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