Apoptosis reprogramming triggered by splicing inhibitors sensitizes multiple myeloma cells to Venetoclax treatment
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
Affiliations
Debora Soncini
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy
Claudia Martinuzzi
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Pamela Becherini
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Elisa Gelli
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy
Samantha Ruberti
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy
Katia Todoerti
Hematology, Fondazione Cà Granda IRCCS Policlinico, Milan, Italy
Luca Mastracci
IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy; Department of Integrated Surgical and Diagnostic Sciences, University of Genoa, Italy
Paola Contini
Department of Internal Medicine (DiMI), University of Genoa, Italy
Antonia Cagnetta
IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Antonella Laudisi
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Fabio Guolo
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Paola Minetto
IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Maurizio Miglino
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Sara Aquino
Hematology and Hematopoietic Stem Cell Transplantation Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
Riccardo Varaldo
Hematology and Hematopoietic Stem Cell Transplantation Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
Daniele Reverberi
U.O. Molecular Pathology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
Matteo Formica
IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy; Department of Surgical Sciences and Integrated Diagnostic (DISC), University of Genoa, Italy
Mario Passalacqua
Department of Experimental Medicine, University of Genoa, Italy
Alessio Nencioni
IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy; Department of Internal Medicine (DiMI), University of Genoa, Italy
Antonino Neri
Hematology, Fondazione Cà Granda IRCCS Policlinico, Milan, Italy; Department of Oncology and Haemato-oncology, University of Milan, Milan, Italy.
Mehmet K. Samur
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Nikhil C. Munshi
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Mariateresa Fulciniti
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
Roberto M. Lemoli
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Michele Cea
Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy
Identification of novel vulnerabilities in the context of therapeutic resistance is emerging as a 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 from healthy donors, with its pharmacological and genetic modulation resulting in impaired growth and survival of MM cell lines and patient-derived malignant plasma cells. Consistent with this, transcriptomic analysis revealed deregulation of BCL2 family members, including decrease of anti-apoptotic 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.
