The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment

Leukemia ◽  
2016 ◽  
Vol 31 (7) ◽  
pp. 1570-1581 ◽  
Author(s):  
F Fan ◽  
M H Bashari ◽  
E Morelli ◽  
G Tonon ◽  
S Malvestiti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Drug Resistance ◽  
Transcription Factor ◽  
Myeloma Cell ◽  
Bone Marrow Microenvironment ◽  
Multiple Myeloma Cell

scholarly journals CD28-mediated regulation of multiple myeloma cell proliferation and survival

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 5002-5010 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Anne M. King ◽  
Despina Kolonias ◽  
Louise M. Carlson ◽  
Hong Yu Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Cell Survival ◽  
Plasma Cells ◽  
Cell Interaction ◽  
Myeloma Cell ◽  
Serum Starvation ◽  
Costimulatory Receptor ◽  
Multiple Myeloma Cell

Abstract Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NFκB, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)–induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM.

Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 703-705 ◽  
Author(s):  
Teru Hideshima ◽  
Masaharu Akiyama ◽  
Toshiaki Hayashi ◽  
Paul Richardson ◽  
Robert Schlossman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Growth ◽  
P38 Mapk ◽  
Myeloma Cell ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Multiple Myeloma Cell ◽  
Mitogen Activated Protein

p38 mitogen-activated protein kinase (MAPK) is a member of the MAPK family which is activated by cytokines and growth factors, but its role in pathogenesis of multiple myeloma (MM) is unknown. In this study, we demonstrate that the specific p38 MAPK inhibitor VX-745 inhibits interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) secretion in bone marrow stromal cells (BMSCs), without affecting their viability. Tumor necrosis factor alpha (TNF-α)–induced IL-6 secretion in BMSCs is also inhibited by VX-745. Importantly, VX-745 inhibits both MM cell proliferation and IL-6 secretion in BMSCs triggered by adherence of MM cells to BMSCs, suggesting that it can inhibit paracrine MM cell growth in the BM milieu and overcome cell adhesion–related drug resistance. These studies therefore identify p38 MAPK as a novel therapeutic target to overcome drug resistance and improve patient outcome in MM.

scholarly journals Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in xenografted mice

Leukemia ◽  
2017 ◽  
Vol 31 (10) ◽  
pp. 2114-2121 ◽  
Author(s):  
D Wang ◽  
Y Fløisand ◽  
C V Myklebust ◽  
S Bürgler ◽  
A Parente-Ribes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Autologous Bone Marrow ◽  
Myeloma Cell ◽  
Th Cells ◽  
Multiple Myeloma Cell ◽  
Autologous Bone ◽  
Proliferation In Vitro

The AP-1 Transcription Factor JunB Promotes Multiple Myeloma (MM) Cell Proliferation, Survival and Drug Resistance in the Bone Marrow Microenvironment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3446-3446 ◽  
Author(s):  
Fengjuan Fan ◽  
Sonia Vallet ◽  
Martin Sattler ◽  
Giovanni Tonon ◽  
Muhammad Hasan Bashari ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Drug Resistance ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Gene Set Enrichment Analysis ◽  
Inhibition Of Proliferation ◽  
Hodgkin's Lymphomas

Abstract MEK/ERK and NF-kB signaling pathways have been reported to play a key role in multiple myeloma (MM) survival, proliferation and drug resistance. These pathways regulate the activity of numerous transcription factors. For example, the activator protein-1 (AP-1) transcription factor has been implicated in a multitude of physiologic processes, but also tumorigenesis. However, the function of AP-1 in MM is largely unknown. Our data show a vast variety of AP-1 (c-Jun, JunB, JunD, c-Maf and c-Fos) expression levels in MM cells. Importantly, co-culture of MM cells with bone marrow stromal cells (BMSCs), i.e. isotypic primary BMSCs as well as BMSC lines KM-105 and HS-27A, rapidly and strongly induces expression of JunB, but not other AP-1 members. Previous studies have shown that JunB exerts opposite functions depending on the cellular origin and the physiopathological context. For example, it serves as a gatekeeper in acute and chronic myeloid leukemia, but as a positive regulator in Hodgkin's lymphomas and anaplastic large cell lymphomas. The relevance of JunB activity in MM growth, survival and drug resistance is elusive. First, our data demonstrate that induction of JunB is predominantly mediated by soluble factors secreted by BMSCs rather than direct MM-BMSC contact. Indeed, using cytokine arrays, we identified IL-6 among the most potent factors that trigger JunB expression. Mechanistically, JunB upregulation occurs at both transcriptional as well as translational level. Pharmacologic inhibition was used next in order to identify upstream signaling pathways, which mediate BMSC- induced JunB upregulation in MM cells. Our data show that activation of MEK/ERK or NF-kB is required for induction of JunB expression and AP-1 transcriptional activity. To delineate the specific functional role of JunB in MM pathogenesis, we transduced MM cells with pLKO.1-JunB shRNA or pLKO.1-scrambled shRNA (SCR). After puromycin- selection, effects of JunB knockdown on MM proliferation, survival and drug resistance were analyzed by 3H-thymidine incorporation, flow cytometry and western blot. Indeed, we observed significant inhibition of proliferation in MM/ JunB shRNA (decreased to ~ 25 – 40 %, p < 0.01) compared with MM/ SCR control cells, when co-cultured with BMSCs in particular. Moreover, our preliminary data show that knockdown of JunB overcomes resistance of MM cells against doxorubicin as well as melphalan. Furthermore, 4-hydroxytamoxifen (4-OHT) treatment of MM cell lines stably transduced with pMSCV-JunB-ER-IRES-GFP but not pMSCV-IRES-GFP induced significant AP-1 luciferase activity (~ 3.3 fold, p < 0.01) as well as MM cell proliferation. In ongoing experiments, the in vivo relevance of our in vitro data is evaluated in a xenograft mouse model inoculated with MM /JunB-ER-IRES-GFP and MM/ IRES-GFP cells. Finally, gene expression profiles on > 1000 MM patient samples of different prognostic groups were compared to samples from healthy donors using the gene set enrichment analysis (GSEA). Our results further support a key role for JunB in MM pathogenesis. In summary, our data demonstrate for the first time an important role of JunB/AP-1 in MM tumorigenesis and strongly propose it as a novel therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.

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