<i>PARP1</i> and <i>POLD2</i> as prognostic biomarkers for multiple myeloma in autologous stem cell transplant

Abstract

Multiple Myeloma (MM) is an incurable plasma cell malignancy often treated by autologous stem cell transplant (ASCT). Clinical response to ASCT has been associated with DNA repair efficiency. Here we interrogated the role of the base excision DNA repair (BER) pathway in MM response to ASCT. Across 450 clinical samples and six disease stages, expression levels of genes in the BER pathway were found to be highly upregulated during the development of MM. In a separate cohort of 559 patients with MM treated with ASCT, expression of BER pathway members MPG and PARP3 was positively associated with overall survival (OS) while expression of PARP1, POLD1, and POLD2 was negatively associated with OS. In a validation cohort of 356 patients with MM treated with ASCT, PARP1 and POLD2 findings were replicated. In patients with MM who never received ASCT (n=319), PARP1 and POLD2 were not associated with OS, suggesting that the prognostic effect of these genes may be treatmentdependent. In pre-clinical models of MM, synergy was observed in anti-tumor activity when poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib, talazoparib) were used in combination with melphalan. The negative prognosis associated with PARP1 and POLD2 expression along with the apparent melphalan sensitizing effect of PARP inhibition may suggest this pathway as a potential biomarker in patients with MM in the setting of ASCT. Further understanding of the role of the BER pathway in MM is vital to improve therapeutic strategies related to ASCT.

A Risk Stratification System in Myeloma Patients with Autologous Stem Cell Transplantation

“…There are some guidelines with which to evaluate whether patients are suitable for ASCT therapy, such as age, performance status, and comorbidities (especially kidney dysfunction), which are used for short-term risk events. For long-term benefits, there have been some risk factor studies, including lymphocytes after ASCT [ 33 ], expression of PARP1 and POLD2 [ 34 ], very good partial response (VGPR) [ 35 ], minimal residual disease [ 36 , 37 ], and PET/CT scan near day 100 post-ASCT [ 38 ]. These indices, whether before or after ASCT, provide information about ASCT patients’ long-term benefits.…”

The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma

“…Also, researchers found that high expressions of certain BER genes, such as MPG (Nmethylpurine DNA glycosylase) and PARP3 [Poly (ADP-ribose) polymerase 3], are linked to improved overall survival in MM patients who received autologous stem cell transplantation. On the other hand, increased expressions of PARP1 and POLD2 (DNA polymerase delta subunit 2) are associated with worse outcomes in MM, suggesting that targeting BER pathway might improve treatment effectiveness [19][20][21]. Moreover, the gene expression patterns in normal plasma cells and newly diagnosed MM samples reveal that upregulation of the Nucleotide Excision Repair (NER) protein ERCC3 (excision repair cross-complementation group 3) is linked to poorer survival.…”

Long non-coding RNA LIP interacts with PARP-1 influencing the efficiency of base excision repair

“…Although discovered in 1974, decades of research have only begun to reveal the broader framework of BER, leaving the specific regulatory network and individual regulatory mechanisms of related proteins largely unresolved [ 13 ]. Key biomolecules participating in the BER pathway include XRCC1 as a repair scaffold [ 14 , 15 ], DNA polymerase β (pol-β), DNA ligase 1, DNA ligase 3, and PARP-1 [ 16 , 17 ]. Among them, PARP-1 plays a pivotal role in the BER pathway.…”