The Notch signaling pathway plays a crucial role in the tumor microenvironment. We examined the expression of Notch receptors (Notch1, Notch2, Notch3, and Notch4) and its ligands (JAG1, JAG2, DLL1, DLL3, and DLL4) in multiple myeloma (MM) cells and the functions of Notch signaling in disease progression. NOTCH1, NOTCH2, and JAG1 mRNA were highly expressed in 17 MM cell lines and primary MM cells from 28 patients, although mRNA levels of NOTCH1 were significantly lower than those of NOTCH2. However, anti-Notch1 antibody inhibited MM cell proliferation and increased the percentage of bortezomib-induced apoptotic MM cells as compared with isotype control and cells cultured with anti-Notch2 antibody. Furthermore, Notch1+ MM cells showed greater proliferative potential and decreased drug susceptibility compared with Notch– cells. Aggressive disease behaviors in Notch1+ MM cells were suppressed by anti-JAG1 antibody. Furthermore, gene expression in Notch1+ cells showed upregulation of p21 and CCND1/2 and downregulation of apoptotic genes compared with those in Notch– cells. Those results demonstrate that the Notch1–JAG1 signaling pathway confers a high malignant potential, suggesting that its Notch signaling may be specifically associated with MM disease progression.
We herein describe a 52-year-old man with multiple myeloma (MM) who developed progressive multifocal leukoencephalopathy (PML). He was diagnosed with MM in December 20XY, and underwent high-dose chemotherapy followed by autologous stem cell transplantation. He relapsed in October 20XY+2, and he was treated with the oral administration of cyclophosphamide and prednisolone (CP). He developed apraxia and visual disturbance in March 20XY+4. Since PML was suspected, we stopped CP and mirtazapine was initiated; however, his neurological symptoms did not improve. He was diagnosed with PML based on John Cunningham virus (JCV) DNA in his cerebrospinal fluid (CSF). He was treated with therapy involving of mirtazapine, cytarabine, and high-dose immunoglobulin; however, his neurological disorders did not improve despite the disappearance of JCV DNA in his CSF. Therefore, we started combination therapy of mirtazapine and mefloquine, which resulted in the significant improvement of both his neurological symptoms and MRI findings. Although we restarted the anti-MM treatment, his neurological symptoms remained stable for more than 2 years with the continuation of this combination therapy. The present case suggests that combination therapy of mirtazapine and mefloquine is effective for patients with PML, particularly those requiring immunosuppressive chemotherapy.
Multiple myeloma (MM) is a refractory hematological malignant neoplasm derived from plasma cells. It has been extensively studied in the quest to develop treatment strategies. Furthermore, several factors of the bone marrow microenvironment could be candidates for novel therapeutic targets. Among these, the hypoxic response is the most important factor maintaining cell homeostasis, and is generally considered as a therapeutic target for various cancers including MM. Although oxygen partial pressure of bone marrow is 50–55 mmHg, that of hypoxic niche is less than 10 mmHg. Myeloma cells adapting to the hypoxic niche exhibit changes in gene expression via activation of hypoxia-inducible factor (HIF), and subsequently acquiring treatment resistance. However, because of its negative effects on normal cells and tissues, HIF inhibitor is not used in medical practice. Hence, downstream targets of HIF should be investigated. In particular, changes induced by the hypoxic response, such as metabolic pathways, cell dissemination, and malignant bone marrow environment, may be promising therapeutic targets. Therefore, future studies should focus on identifying therapeutic drugs targeting hypoxic environments and hypoxia-inducible genes.