Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance

Colombo, M.; Garavelli, S.; Mazzola, Mara; Platonova, N.; Giannandrea, Domenica; Colella, R.; Apicella, L.; Lancellotti, M.; Lesma, Elena; Ancona, Silvia; Palano, Maria Teresa; Barbieri, Marzia; Taìana, Elisa; Lazzari, Elisa; Basile, Andrea; Turrini, Mauro; Pistocchi, Anna; Neri, Antonino; Chiaramonte, R.

doi:10.3324/haematol.2019.221077

Cited by 21 publications

(28 citation statements)

References 51 publications

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“…Both IAP proteins inhibit the executioner caspases-3 and -7, and XIAP additionally inhibits caspase-9. In the MM BM-ME, MSCs can upregulate both XIAP and Survivin in MM and other tumors [72][73][74][75][76] through the stimulation of NF-κB signaling [66,77], downregulation of the Survivin-targeting microRNA miRNA-101-3p [74] or through NOTCH signaling [78][79][80][81].…”

Section: Inhibition Of Apoptosis By the Bm-mementioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

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Section: Inhibition Of Apoptosis By the Bm-mementioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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“…To assess the involvement of MM cell-derived Jagged ligands in angiogenesis promotion, we knocked down (KD) the ligands in two human myeloma cell lines (HMCLs), namely RPMI8226 and OPM2, by using siRNAs targeting Jagged1 or Jagged2 (HMCLs KD ) or the corresponding scrambled siRNA as the control (HMCLs SCR ), as previously reported [ 6 , 10 ]. We assessed the KD efficacy on Jagged1 and 2 mRNA as well as on the Notch transcriptional targets by using quantitative qRT-PCR ( Figure 1 A, upper panel) and confirmed the downregulation of the corresponding protein levels by Western blotting ( Figure 1 A, lower panel).…”

Section: Resultsmentioning

confidence: 99%

“…The Notch pathway plays a relevant role in MM development and progression, mediating the communication between the MM cells and the surrounding cell population of the BM microenvironment, including the BMSCs [ 10 , 11 ] and osteoclasts [ 12 ]. This interplay is possibly due to the increased expression of the Jagged ligands on the MM cell surface.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, Jagged2 is already expressed at higher levels in the benign MGUS phase [ 13 ], while Jagged1 upregulation occurs later during the progression to the symptomatic MM [ 14 ]. Jagged ligands’ increase leads to the aberrant activation of the Notch signaling, not only in MM cells through homotypic interaction, but also in the surrounding BM cells via heterotypic interaction [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells

Palano

Giannandrea

Platonova

et al. 2020

Cancers

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Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1–2 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines’ ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients’ BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands.

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“…The use of bisphosphonates is intended for the management of patients with osteolytic bone disease [5,6]. However, MM, unfortunately, remains an incurable disease associated with a high mortality rate, due to late diagnosis [7,8] or resistance to pharmacological treatments [9,10].…”

Section: Introductionmentioning

confidence: 99%

Emerging Insights on the Biological Impact of Extracellular Vesicle-Associated ncRNAs in Multiple Myeloma

Raimondo

Urzì

Conigliaro

et al. 2020

ncRNA

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Increasing evidence indicates that extracellular vesicles (EVs) released from both tumor cells and the cells of the bone marrow microenvironment contribute to the pathobiology of multiple myeloma (MM). Recent studies on the mechanisms by which EVs exert their biological activity have indicated that the non-coding RNA (ncRNA) cargo is key in mediating their effect on MM development and progression. In this review, we will first discuss the role of EV-associated ncRNAs in different aspects of MM pathobiology, including proliferation, angiogenesis, bone disease development, and drug resistance. Finally, since ncRNAs carried by MM vesicles have also emerged as a promising tool for early diagnosis and therapy response prediction, we will report evidence of their potential use as clinical biomarkers.

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Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance

Cited by 21 publications

References 51 publications

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Jagged Ligands Enhance the Pro-Angiogenic Activity of Multiple Myeloma Cells

Emerging Insights on the Biological Impact of Extracellular Vesicle-Associated ncRNAs in Multiple Myeloma

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