Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Olga Ostrovsky; Katia Beider; Hila Magen; Merav Leiba; Ralph D Sanderson; Israel Vlodavsky; Arnon Nagler

doi:10.3390/cells12060913

Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

Cells. 2023 Mar 16;12(6):913. doi: 10.3390/cells12060913.

Authors

Olga Ostrovsky¹, Katia Beider¹, Hila Magen¹, Merav Leiba¹, Ralph D Sanderson², Israel Vlodavsky³, Arnon Nagler¹

Affiliations

¹ Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer 5266202, Israel.
² Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
³ Technion Integrated Cancer Center (TICC), Rappaport Faculty of Medicine, Technion, Haifa 3525433, Israel.

Abstract

Multiple myeloma (MM) is a plasma cell malignancy that is accompanied by hypercalcemia, renal failure, anemia, and lytic bone lesions. Heparanase (HPSE) plays an important role in supporting and promoting myeloma progression, maintenance of plasma cell stemness, and resistance to therapy. Previous studies identified functional single nucleotide polymorphisms (SNPs) located in the HPSE gene. In the present study, 5 functional HPSE SNPs and 11 novel HPSE2 SNPs were examined. A very significant association between two enhancer (rs4693608 and rs4693084), and two insulator (rs4364254 and rs4426765) HPSE SNPs and primary paraskeletal disease (PS) was observed. SNP rs657442, located in intron 9 of the HPSE2 gene, revealed a significant protective association with primary paraskeletal disease and lytic bone lesions. The present study demonstrates a promoting (HPSE gene) and protective (HPSE2 gene) role of gene regulatory elements in the development of paraskeletal disease and bone morbidity. The effect of signal discrepancy between myeloma cells and normal cells of the tumor microenvironment is proposed as a mechanism for the involvement of heparanase in primary PS. We suggest that an increase in heparanase-2 expression can lead to effective suppression of heparanase activity in multiple myeloma accompanied by extramedullary and osteolytic bone disease.

Keywords: HPSE gene; HPSE2 gene; SNPs; extramedullary disease; multiple myeloma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bone Diseases / genetics
Glucuronidase* / genetics
Humans
Introns
Multiple Myeloma* / genetics
Polymorphism, Single Nucleotide / genetics
Tumor Microenvironment

Substances

Glucuronidase
heparanase

Grants and funding

We wish to thank the Naor family for a generous research grant memorizing their dear son-in-law, Mr. Guy Weinshtock, with “The Guy Weinshtock Multiple Myeloma Foundation”, in support of research in the field of MM at the Division of Hematology at the Chaim Sheba Medical Center, Tel Hashomer, Israel. We acknowledge the support of the US-Israel-Binational Science Foundation (BSF 2021059) awarded to Israel Vlodavsky (Technion) and Ralph D. Sanderson (UAB), and the DKFZ-MOST cooperation cancer research program.