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4145 C17ORF58 Is Upregulated in Peripheral T-Cell Lymphomas and Encodes a Protein Critical for Survival of PTCL Cells

Program: Oral and Poster Abstracts
Session: 603. Lymphoid Oncogenesis: Basic: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, apoptosis, Lymphomas, non-Hodgkin lymphoma, T Cell lymphoma, Diseases, Lymphoid Malignancies, Biological Processes, molecular biology
Monday, December 11, 2023, 6:00 PM-8:00 PM

Julian Tobon, BS1,2*, Pawel Nowialis, PhD1,2,3*, Katarina Lopusna, PhD1,2,4*, Duo Chen, MS1,2*, Arshee Badar, MD1,2*, Reem Abdelghany5*, Emma Noel6*, Jacob Fingeret5*, Gene Pozas5*, Jana Opavska, MS1,2*, Hiroshi Fujiwara, MD, PhD7 and Rene Opavsky, PhD1,2

1Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL
2UF NCI-designated Cancer Center, University of Florida, Gainesville, FL
3Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX
4Department of Microbiology and Virology, Comenius University, Bratislava, Slovakia
5UF College of Liberal Arts and Sciences, University of Florida, Gainesville, FL
6College of Agriculture and Life Sciences, University of Florida, Gainesville, FL
7Ehime University, School of Medicine, Tsu, MIE, JPN

Peripheral T-cell lymphomas (PTCL) constitute a group of heterogeneous T- and NK-cell malignancies, accounting for about 15% of Non-Hodgkin lymphomas (NHL). Most PTCL subtypes exhibit an aggressive disease presentation, carrying a worse prognosis than B-cell lymphomas. PTCL – Not Otherwise Specified (PTCL-NOS), the largest subgroup, is categorized by exclusion, with a diagnosis given if the patient does not meet the diagnostic criteria of other PTCL subtypes. PTCL-NOS is a heterogeneous group with diverse cells of origin, varied cytogenic, molecular, and morphological phenotypes, and antigen variability. Despite the increase in specific T-cell lymphoma treatment options, such as belinostat, romidepsin, pralatrexate, and brentuximab vedotin, alongside conventional non-targeted chemotherapy like CHOP and R-CHOP, the overall 5 year survival remains only at 20-30%. A deeper understanding of the pathways and genes critical for PTCL-NOS survival is urgently needed.

In our quest to better understand the molecular landscape, we performed a gene expression analysis of ten PTCL-NOS lymphomas and five normal samples using RNAseq analysis. Our study identified ~400 genes consistently upregulated in lymphoma samples, indicating potential involvement in tumor maintenance. Following the exclusion of common essential genes, we performed a shRNA-mediated knockdown screen of the remaining candidates in the human PTCL-NOS cell line T8ML-1. This approach unveiled several lethal genes, including MYBL2, TRIP13, KIF18B, C17ORF58, and others. Cell cycle analysis demonstrated that while knockdown of MYBL2, TRIP13, and KIF18B induced G2-M arrest, downregulation of C17ORF58 primarily induced apoptosis. Notably, downregulation of C17ORF58 did not impact the proliferation of human embryonic kidney fibroblasts HEK 293T, suggesting that normal cells might not require this protein for growth. However, its downregulation in additional hematologic cell lines, such as Cutaneous T-cell lymphoma cell lines (HH, Hut78) and T-cell lymphoblastic leukemia (Jurkat), also induced apoptosis, which suggests a key role for C17ORF58 in T-cell malignancies. Analysis of publicly available RNAseq data revealed overexpression of C17ORF58 in the majority of PTCL-NOS, Anaplastic Large Cell, Hepatosplenic T-cell, and malignant NK/T-cell lymphomas, relative to normal T-cells, thus highlighting its possible role in tumor development and maintenance.

C17ORF58 encodes a predicted protein of 339 amino acids, with an estimated molecular weight of 37 kDa. This protein features two putative domains: the PRK07764 domain, which is homologous to DNA polymerase III subunits gamma and tau, and the netrin module, a 130 amino acid residue domain found within the C-terminal sections of various proteins, including netrins, complement proteins C3-C5, secreted frizzled-related proteins, and type I procollagen C-proteinase enhancer proteins. The predicted promoter has binding sites for Oct-B1-3, Pax-2, POU2F1-2, 2B, and 2C, suggesting that the C17ORF58-encoded protein may participate in normal development.

In conclusion, our data indicate that upregulation of C17ORF58 may contribute to the progression and maintenance of PTCL and could serve as a potential target for treating T-cell malignancies. Investigations into its physiological role in normal T-cells and pathways deregulated upon its inactivation are ongoing.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH