Assessment of TP53 lesions for p53 system functionality and drug resistance in multiple myeloma using an isogenic cell line model

Abstract

Recent advances in molecular diagnostics have shown that lesions affecting both copies of the gene for tumor suppressor protein 53 (TP53) count among the most powerful predictors for high-risk disease in multiple myeloma (MM). However, the functional relevance and potential therapeutic implications of single hits to TP53 remain less well understood. Here, we have for the first time approximated the different constellations of mono- and bi-allelic TP53 lesions observed in MM patients within the frame of a single MM cell line model and assessed their potential to disrupt p53 system functionality and to impart drug resistance. Both types of common first hit: point mutation with expression of mutant p53 protein or complete loss of contribution from one of two wildtype alleles strongly impaired p53 system functionality and increased resistance to melphalan. Second hits abolished remaining p53 activity and increased resistance to genotoxic drugs even further. These results fit well with the clinical drive to TP53 single- and double-hit disease in MM patients, provide a rationale for the most commonly observed double-hit constellation (del17p+ TP53 point mutation), and underscore the potential increases in MM cell malignancy associated with any type of initial TP53 lesion.

Long non‐coding RNA NEAT1 serves as a novel biomarker for treatment response and survival profiles via microRNA‐125a in multiple myeloma

“…Following that, the related analysis indicated that lncRNA NEAT1 was negatively associated with CR, ORR, PFS, and OS in MM patients, suggesting the potential of lncRNA NEAT1 as a prognostic biomarker in MM. The possible reason might be that according to the prior studies, lncRNA NEAT1 is involved in p53‐dependent DNA damage response network, which has connection with increased chemotherapy resistance in MM patients 21,27 . Furthermore, considering our data that patients with high lncRNA NEAT1 expression presented poor systematic disease condition, MM patients with high lncRNA NEAT1 had poor treatment response and unfavorable survival.…”

“…The possible reason might be that according to the prior studies, lncRNA NEAT1 is involved in p53-dependent DNA damage response network, which has connection with increased chemotherapy resistance in MM patients. 21,27 Furthermore, considering our data that patients with high lncRNA NEAT1 expression presented poor systematic disease condition, MM patients with high lncRNA NEAT1 had poor treatment response and unfavorable survival.…”

Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies—Current Research and Clinical Approaches

“…By contrast, in a cohort of patients with relapsed MM, TP53 abnormalities were identified in 45% of the patients, and the double hit event del(17p)/TP53mut or del(17p)/TP53del was present in 15% of the cases [112,113]. Second hits (del17p+ TP53 point mutation) abolish the remaining p53 activity and increase resistance to melphalan [110]. Deletions of chromosome 17p13 in TP53 result in shorter median event-free survival (EFS) (14.6 months) and median OS (22.4 months) [114].…”

“…DNA damage in peripheral blood mononuclear cells is a predictor of clinical outcome in patients treated with high-dose melphalan and ASCT [109]. Moreover, genetic lesions affecting both alleles of the tumor suppressor gene TP53 are major indicators of unfavorable prognosis in newly diagnosed MM [110]. Only 3.7% of patients are diagnosed with biallelic changes in the TP53 gene in the form of a loss or mutation (called double-hit myeloma) [111].…”

“…Deletions of chromosome 17p13 in TP53 result in shorter median event-free survival (EFS) (14.6 months) and median OS (22.4 months) [114]. Increasingly accurate diagnostics of tumors in terms of damage to the TP53 gene will facilitate therapeutic decisions that are beneficial for the patient [110].…”