Prognostic significance of esterase gene expression in multiple myeloma

Romika Kumari,Muntasir Mamun Majumder,Juha Lievonen,Pekka Anttila,Caroline A Heckman,Raija Silvennoinen,Nina N Nupponen,Fredrik Lehmann

doi:10.1038/s41416-020-01237-1

Abstract

BackgroundEsterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM).MethodsFor gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). CD138+ plasma cells were enriched and used for RNA sequencing and analysis, and to evaluate genomic variation. The Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) dataset was used for validation of the findings from FIMM.ResultsMM patients (NDMM, n = 56; RRMM, n = 78) provided 171 bone marrow aspirates (NDMM, n = 56; RRMM, n = 115). Specific esterases exhibited relatively high or low expression in MM, and expression of specific esterases (UCHL5, SIAE, ESD, PAFAH1B3, PNPLA4 and PON1) was significantly altered on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, SIAE and USP4, and low expression of PCED1B, were identified as poor prognostic markers (P < 0.05). The MMRF CoMMpass dataset provided validation that higher expression of PAFAH1B3 and SIAE, and lower expression of PCED1B, were associated with poor prognosis.ConclusionsEsterase gene expression levels change as patients progress from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology.

Highlights

Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer
We demonstrate that specific esterases exhibit relatively high or low expression in multiple myeloma, that the esterase expression profile changes on the progression of the disease, and that high or low expression of individual esterases is associated with poor prognosis
Sample collection and plasma cell enrichment For gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from multiple myeloma patients after obtaining written informed consent and following protocols approved by an ethical committee of the Helsinki University Hospital Comprehensive Cancer Center, and in compliance with the Declaration of Helsinki

Summary

Introduction

Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology. Both antibody–drug conjugates (ADCs) and peptide–drug conjugates (PDCs) represent important therapeutic classes that enable the selective introduction of cytotoxic drugs into cancer cells over healthy cells, potentially improving efficacy and reducing systemic toxicity compared with non-conjugated versions of the same drug.[1,2] Conceptual similarities between ADCs and PDCs include selective targeting and subsequent cellular internalisation, the exact mechanism of action is specific to each individual conjugate. Hydrolysing enzymes can be highly expressed in cancer cells, and have previously been implicated in the reprogramming of metabolic pathways, promotion of cancer pathogenesis, drug metabolism and drug toxicity.[4,5] Esterases expressed in tumour cells may differ in their stereoselectivity for hydrolysis of chiral esters compared with esterases expressed in healthy tissues.[6,7,8,9] Esterases can themselves be administered to treat haematological malignancies; for example, the enzyme asparaginase has been used as an effective agent to treat acute lymphoblastic leukaemia for many years,[10] and it is being investigated for the treatment of acute myeloid leukaemia.[11]

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