Significance of hematopoietic surface antigen CD34 in neuroblastoma prognosis and the genetic landscape of CD34-expressi
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ORIGINAL ARTICLE
Significance of hematopoietic surface antigen CD34 in neuroblastoma prognosis and the genetic landscape of CD34-expressing neuroblastoma CSCs Natarajan Aravindan & Dinesh Babu Somasundaram & Terence S. Herman Aravindan
&
Sheeja
Received: 9 June 2020 / Accepted: 16 September 2020 # Springer Nature B.V. 2020
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+
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 NMYC amplification. • Comparative gene expression profile of CD34+ NB CSCs recognized activated signaling pathways and cellular functions that correspond to disease evolution. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10565-020-09557-x) contains supplementary material, which is available to authorized users. N. Aravindan (*) : D. B. Somasundaram : T. S. Herman Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, BMSB 737, 940 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA e-mail: [email protected] N. Aravindan Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA N. Aravindan Department of Anesthesiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA T. S. Herman : S. Aravindan Stephenson Cancer Center, Oklahoma City, OK 73104, USA
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 posttransplant 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 CD34expressing 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 CD3
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