Transcriptomic Analysis in Multiple Myeloma and Primary Plasma Cell Leukemia with t(11;14) Reveals Different Expression Patterns with Biological Implications in Venetoclax Sensitivity.

Katia Todoerti,Elisa Taiana,Massimo Gentile,Noemi Puccio,Umberto Gianelli,Marta Lionetti,Ilaria Silvestris,Luca Baldini,Fortunato Morabito,Vanessa Favasuli,Pellegrino Musto,Niccolò Bolli,Domenica Ronchetti,Antonino Neri

doi:10.3390/cancers13194898

Abstract

Simple SummaryThe growing interest in BCL2 inhibitors for the treatment of multiple myeloma (MM) has led to the need for biomarkers that are able to predict patient’s sensitivity to the drug. The presence of the chromosomal translocation t(11;14) in MM is mainly associated with sensitivity to venetoclax and good prognosis. The incidence of t(11;14) largely increases in primary Plasma Cell Leukemia (pPCL) in association with an unfavorable outcome. Currently, data concerning pPCL sensitivity to venetoclax are virtually absent. In this context, we investigated the transcriptome of MM and pPCL with t(11;14), evidencing that the two clinical entities are likely responsive to venetoclax based on different molecular programs, thus prompting further studies to elucidate better novel potential predictive biomarkers.Mechanisms underlying the pathophysiology of primary Plasma Cell Leukemia (pPCL) and intramedullary multiple myeloma (MM) need to be further elucidated, being potentially relevant for improving therapeutic approaches. In such a context, the MM and pPCL subgroups characterized by t(11;14) deserve a focused investigation, as the presence of the translocation is mainly associated with sensitivity to venetoclax. Herein, we investigated a proprietary cohort of MM and pPCL patients, focusing on the transcriptional signature of samples carrying t(11;14), whose incidence increases in pPCL in association with an unfavorable outcome. In addition, we evaluated the expression levels of the BCL2-gene family members and of a panel of B-cell genes recently reported to be associated with sensitivity to venetoclax in MM. Moreover, transcriptional analysis of lncRNAs in the two clinical settings led to the identification of several differentially expressed transcripts, among which the SNGH6 deregulated lncRNA might be relevant in the pathogenesis and prognosis of pPCL with t(11;14). Overall, our data suggest that MMs and pPCLs with t(11;14) might be responsive to venetoclax based on different molecular programs, prompting further studies to elucidate better novel potential predictive biomarkers.

Highlights

Multiple myeloma (MM) is a malignant proliferation of antibody-secreting bonemarrow plasma cells (PCs) that is characterized by a highly heterogeneous genetic background with structural chromosomal aberrations and specific gene mutations [1]
We focused our further studies on protein-coding genes and lncRNAs
Our study focused on the expression levels of the BCL2 gene family and of a panel of B-cell genes associated with venetoclax sensitive MM [19] in both MMs and primary Plasma Cell Leukemia (pPCL) stratified for the presence of t(11;14)

Summary

Introduction

Multiple myeloma (MM) is a malignant proliferation of antibody-secreting bonemarrow plasma cells (PCs) that is characterized by a highly heterogeneous genetic background with structural chromosomal aberrations and specific gene mutations [1]. Mechanisms underlying pPCL pathophysiology compared to intramedullary MM need to be further elucidated, being potentially relevant for improving therapeutic approaches. In such a context, the MM and pPCL subgroups characterized by t(11;14) deserve a focused investigation as the presence of the translocation is mainly associated with sensitivity to venetoclax, a highly potent selective BCL2 inhibitor capable of inducing apoptosis in cells dependent upon BCL2 for survival [18]

Methods

Results

Conclusion