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Plasma Cell Disorders
Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance
Ferrata Storti Foundation
Haematologica 2020 Volume 105(7):1925-1936
Michela Colombo,1 Silvia Garavelli,1 Mara Mazzola,2 Natalia Platonova,1 Domenica Giannandrea,1 Raffaella Colella,1 Luana Apicella,1
Marialuigia Lancellotti,1 Elena Lesma,1 Silvia Ancona,1 Maria Teresa Palano,1 Marzia Barbieri,3,4 Elisa Taiana,3,4 Elisa Lazzari,1 Andrea Basile,3 Mauro Turrini,5 Anna Pistocchi,2 Antonino Neri3,4 and Raffaella Chiaramonte1
1Department of Health Sciences, Università degli Studi di Milano, Milano; 2Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano; 3Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milano; 4Hematology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milano and 5Department of Hematology, Division of Medicine, Valduce Hospital, Como, Italy
ABSTRACT
Multiple myeloma is still incurable due to an intrinsic aggressiveness or, more frequently, to the interactions of malignant plasma cells with the bone marrow (BM) microenvironment. Myeloma cells educate BM cells to support neoplastic cell growth, survival, acquisition of drug resistance resulting in disease relapse. Myeloma microenvironment is characterized by Notch signaling hyperactivation due to the increased expression of Notch1 and 2 and the ligands Jagged1 and 2 in tumor cells. Notch activation influences myeloma cell biology and promotes the repro- gramming of BM stromal cells. In this work we demonstrate, in vitro, ex vivo and by using a zebrafish multiple myeloma model, that Jagged inhibition causes a decrease in both myeloma-intrinsic and stromal cell-induced resist- ance to currently used drugs, i.e. bortezomib, lenalidomide and melphalan. The molecular mechanism of drug resistance involves the chemokine sys- tem CXCR4/SDF1α. Myeloma cell-derived Jagged ligands trigger Notch activity in BM stromal cells. These, in turn, secrete higher levels of SDF1α in the BM microenvironment increasing CXCR4 activation in myeloma cells, which is further potentiated by the concomitant increased expression of this receptor induced by Notch activation. Consistently with the aug- mented pharmacological resistance, SDF1α boosts the expression of BCL2, Survivin and ABCC1. These results indicate that a Jagged-tailored approach may contribute to disrupting the pharmacological resistance due to intrinsic myeloma cell features or to the pathological interplay with BM stromal cells and, conceivably, improve patients’ response to standard-of-care ther- apies.
Introduction
Multiple myeloma (MM) is the second most common hematologic malignancy. It is still incurable, with a median overall survival that has not been substantially extended since the introduction of anti-myeloma agents such as melphalan, lenalidomide, and bortezomib.1 The typical clinical course of MM displays a remission-relapse pattern due to the appearance of drug-resistant malignant cells, reducing the numbers of effective salvage regimens.2 Therefore, a more stable response requires the development of a therapeutic approach that prevents drug resistance.
Multiple myeloma cells accumulate in the bone marrow (BM), where they establish anomalous signaling loops with BM-residing non-tumor cells, resulting in the exchange of anti-apoptotic factors which critically induce drug resistance.3
The Notch pathway includes four transmembrane receptors (Notch1-4) activat-
Correspondence:
RAFFAELLA CHIARAMONTE
raffaella.chiaramonte@unimi.it
MICHELA COLOMBO
michela.colombo@ndcls.ox.ac.uk
Received: March 10, 2019. Accepted: September 26, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2019.221077
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/7/1925
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