Abstract 190: Prognostic significance of esterase gene expression in multiple myeloma
Authors: Romika Kumari, M. Mamun Majumder, Juha Lievonen, Raija Silvennoinen, Pekka Anttila, Nina N. Nupponen, Fredrik Lehmann, Caroline A. Heckman
Journal: Cancer Research (2020)

Abstract Introduction: The esterase enzyme family is a subclass of the hydrolase enzyme superfamily that functions to split ester bonds. Several esterases have been identified, which differ in substrate specificity and biological function, and the expression of specific esterases may be dysregulated in cancer. Limited information is available regarding the expression of esterases in multiple myeloma (MM), despite potential for exploitation in novel therapeutic approaches such as peptide-drug conjugates (e.g. melflufen). We evaluated the biological significance of esterase enzyme expression in MM. Methods: For gene expression profiling, bone marrow aspirates were obtained from MM patients (pts) or healthy donors after obtaining written informed consent and following approved protocols in compliance with the Declaration of Helsinki. CD138+ plasma cells were enriched and used for RNA preparation. Illumina-compatible RNA sequencing libraries were prepared and sequenced. A cut-off value of &amp;gt;1 Reads Per Kilobase of transcript per Million mapped reads (RPKM) was used to filter expressed genes. The Welch two-sample t-test was used to identify significant variation in gene expression. Contribution of esterase gene expression to survival outcome was estimated by Kaplan-Meier analysis; significance between two groups was deduced using a Mantel-Cox log rank test. Results: Of 123 pts with MM, bone marrow aspirates were collected from 41 pts with newly diagnosed (ND) MM, 81 pts with relapsed/refractory (RR) MM, and 1 pt with stable disease. Samples were also obtained from two healthy donors. The most abundant esterases in MM samples were OVCA2, PAFAH1B2, NXPE3, UCHL3, LIPA, ABHD10, UCHL5, CASD1, ABHD13, and USP4 (median log2[RPKM] range: 3.9 to 2.1). The least abundant esterases were NLGN1, NLGN2, PON1, CEL, PON3, NLGN4Y, IL17A, AADAC, CES5A, and ASPG (median log2[RPKM]: -5.1 to -10.7). The expression levels of OVCA2, PAFAH1B2, NXPE3, UCHL5, SIAE, ESD, PNPLA6, and PAFAH1B3 were significantly higher (P&amp;lt;0.05), and of PCED1B significantly lower (P&amp;lt;0.05), in RRMM versus NDMM. The expression level of all these genes was comparatively higher in the two healthy donor samples. High expression of OVCA2, PAFAH1B3, CES4A, or PNPLA6 was associated with poorer prognosis (overall survival [OS]) versus low expression samples (median OS for high vs low expression [months]: OVCA2: 55 vs 122; PAFAH1B3: 55 vs 124; CES4A: 55 vs not reached; PNPLA6: 89 vs 127; all P≤0.01), whereas low expression of NXPE4 or GZMA was associated with poorer prognosis versus high expression samples (median OS for high vs low expression [months]: NXPE4: 120 vs 55; GZMA: 120 vs 74; both P≤0.03). Conclusion: Esterase expression levels in MM change on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, CES4A, and PNPLA6, and low expression of NXPE4 and GZMA, were identified as poor prognostic markers in pts with MM, suggesting a role for these esterases in myeloma biology. Citation Format: Romika Kumari, M. Mamun Majumder, Juha Lievonen, Raija Silvennoinen, Pekka Anttila, Nina N. Nupponen, Fredrik Lehmann, Caroline A. Heckman. Prognostic significance of esterase gene expression in multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 190.