Myeloid cell factor–1 is a critical survival factor for multiple myeloma

Abstract

IntroductionMultiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of plasma cells with a low proliferation index and an extended life span. 1,2 Despite improvements in event-free and long-term survival resulting from autologous stem cell transplantation, MM remains an incurable disease in the majority of patients. 3,4 In the initial phases of this disease, the malignant plasma cells are dependent on the supportive environment of the bone marrow, which is at least partly responsible for the up-regulation of antiapoptotic factors in the tumor cells. 5,6 Translocations and aneuploidy are detected in the earliest stage of the disease (monoclonal gammopathy of undetermined significance), 7-9 and karyotypic abnormalities accumulate as the disease progresses. 2,10 In the later stages of disease, genetic lesions result in the activation of oncogenes that promote cell growth (Ras) and the loss of tumor suppressors (p16 Ink4a , p53), and the disease becomes bone marrow stroma-independent. 2 The molecular basis for the poor prognosis conferred by other genetic lesions, especially deletions of chromosome 13q, remains to be elucidated. 11 Interleukin-6 (IL-6) is important for the growth and survival 12-14 of myeloma cells and increases resistance to a variety of therapeutic interventions. [15][16][17] Bone marrow (BM) stromal cells provide IL-6 in a paracrine fashion, leading to activation of the Ras/mitogen-activated protein kinase (MAPK) and Jak/signal transducers and activators of transcription (STAT) pathways. 2,18,19 The Ras/MAPK pathway is considered more important for MM cell proliferation 20 ; however, it is likely that downstream effectors of Ras also play a role in cell survival. 21 In some experimental systems, STAT3 has been shown to activate genes that promote MM cell survival, including Bcl-XL and myeloid cell factor-1(Mcl-1). 22,23 Constitutive expression of STAT3 has been demonstrated in freshly isolated MM cells and may confer an important survival advantage in vivo. 22 Expression of antiapoptotic members of the Bcl-2 family appears to be an important factor for the clinical resistance of MM. Five antiapoptotic Bcl-2 family members (Bcl-2, Bcl-XL, A1, Mcl-1, and Bcl-w) have been identified in mammalian cells. [24][25][26] Bcl-2 has been found to be highly expressed in malignant plasma cells. [27][28][29] Bcl-XL expression was detected more frequently in patients at relapse and was shown to correlate with resistance to chemotherapy. 30,31 Mcl-1 is distinct from Bcl-2 and Bcl-XL in that it lacks a BH4 domain and is a large protein (40 kd as compared with 26 kd for Bcl-2) that encodes additional domains with Pro-Glu-Ser-Thr-like sequences (PEST) that could account for its short half-life (although recent data question the importance of the putative Pro-Glu-Ser-Thr sequences in regulating Mcl-1 turnover). [32][33][34] Mcl-1 levels in MM cells were reported to be induced by IL-6 in a STAT3-dependent mechanism. 23 The roles of A1 and Bcl-W in MM remain to be determined. Thus, MM cells expr...

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

“…Mcl-1, which is highly expressed in hematopoietic cells, is an antiapoptotic member of the Bcl-2 family (Craig, 2002). In multiple myeloma (MM) cells, in which IL-6 plays a critical role in proliferation and survival, upregulation of Mcl-1 was shown to mediate the antiapoptotic effect of IL-6 (Jourdan et al, 2003), whereas the downregulation of the gene by antisense technology led to apoptosis (Derenne et al, 2002;Zhang et al, 2002;Le Gouill et al, 2004). In a study conducted on 12 IL-6-dependent human myeloma cell lines, Mcl-1 was found to be the only Bcl-2 family member (out of ten considered in the study) overexpressed in all the cell lines and regulated by IL-6, thus suggesting Mcl-1 as a major mediator of the survival activity of the cytokine (Craig, 2002;Jourdan et al, 2003;Le Gouill et al, 2004).…”

Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma

“…[17][18][19] Therefore, we sought to induce dual inhibition of Mcl-1 by combining a proteasome inhibitor, carfilzomib, with a multikinase inhibitor, TG02. Individually these drugs could induce apoptosis in multiple myeloma cell lines, but in combination they had at least additive effects.…”

“…16 In order for MM cells to resist apoptosis they are dependent on the anti-apoptotic protein Mcl-1 for survival. [17][18][19] Mcl-1 is an oncogene that promotes tumorigenesis by binding to pro-apoptotic proteins Bak and Bim, thus preventing the release of cytochrome c from the mitochondria and subsequent caspase activation. 20 Given that most MM cells are dependent on Mcl-1 for survival it would be beneficial to inhibit Mcl-1 to increase the apoptotic response in these cells.…”

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

“…It is essential for the survival of plasma cells in vitro (Zhang et al, 2002), and overexpressed by those from patients with relapse or poor prognosis (Wuillelme-Toumi et al, 2005).…”