Open AccessApoptosis reprogramming triggered by splicing inhibitors sensitizes multiple myeloma cells to Venetoclax treatment
Author(s) -
Debora Soncini,
Claudia Martinuzzi,
Pamela Becherini,
Elisa Gelli,
Samantha Ruberti,
Katia Todoerti,
Luca Mastracci,
Paola Contini,
Antonia Cagnetta,
Antonella Laudisi,
Fabio Guolo,
Paola Minetto,
Maurizio Miglino,
Sara Aquino,
Riccardo Varaldo,
Daniele Reverberi,
Matteo Formica,
Mario Passalacqua,
Alessio Nencioni,
Antonino Neri,
Mehmet K. Samur,
Nikhil C. Munshi,
Mariateresa Fulciniti,
Roberto M. Lemoli,
Michele Cea
Publication year - 2021
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.279276
Subject(s) - spliceosome , cancer research , venetoclax , mcl1 , biology , rna splicing , context (archaeology) , epigenetics , myeloid leukemia , reprogramming , leukemia , microbiology and biotechnology , cell , chronic lymphocytic leukemia , gene , downregulation and upregulation , immunology , genetics , rna , paleontology
Identification of novel vulnerabilities in the context of therapeutic resistance is emerging as key challenge for cancer treatment. Recent studies have detected pervasive aberrant splicing in cancer cells, supporting its targeting for novel therapeutic strategies. Here, we evaluated the expression of several spliceosome machinery components in multiple myeloma (MM) cells and the impact of splicing modulation on tumor cell growth and viability. A comprehensive gene expression analysis confirmed the reported deregulation of spliceosome machinery components in MM cells, compared to normal plasma cells (PCs) from healthy donors, with its pharmacological and genetic modulation resulting in impaired growth and survival of MM cell lines and patient-derived malignant PCs. Consistent with this, transcriptomic analysis revealed deregulation of BCL2 family members, including decrease of antiapoptotic long form of myeloid cell leukemia-1 (MCL1) expression, as crucial for “priming” MM cells for Venetoclax activity in vitro and in vivo, irrespective of t(11;14) status. Overall, our data provide a rationale for supporting the clinical use of splicing modulators as a strategy to reprogram apoptotic dependencies and make all MM patients more vulnerable to BCL2 inhibitors.