The Evolution and Maintenance of the Multiple Myeloma Cell Clone within the Liquid Bone Marrow Compartment

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.

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CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf–mediated interactions with bone marrow stromal cells

Blood ◽

10.1182/blood-2008-10-183772 ◽

2009 ◽

Vol 113 (18) ◽

pp. 4309-4318 ◽

Cited By ~ 41

Author(s):

Yu-Tzu Tai ◽

Ender Soydan ◽

Weihua Song ◽

Mariateresa Fulciniti ◽

Kihyun Kim ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Molecular Mechanisms ◽

Myeloma Cell ◽

Marrow Stromal Cells ◽

Growth And Survival ◽

Multiple Myeloma Cell

Abstract CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients regardless of cytogenetic abnormalities or response to current treatments. Furthermore, CS1 is detected in MM patient sera and correlates with active disease. However, its contribution to MM pathophysiology is undefined. We here show that CS1 knockdown using lentiviral short-interfering RNA decreased phosphorylation of ERK1/2, AKT, and STAT3, suggesting that CS1 induces central growth and survival signaling pathways in MM cells. Serum deprivation markedly blocked survival at earlier time points in CS1 knockdown compared with control MM cells, associated with earlier activation of caspases, poly(ADP-ribose) polymerase, and proapoptotic proteins BNIP3 and BIK. CS1 knockdown further delayed development of MM tumor and prolonged survival in mice. Conversely, CS1 overexpression promoted myeloma cell growth and survival by significantly increasing myeloma adhesion to bone marrow stromal cells (BMSCs) and enhancing myeloma colony formation in semisolid culture. Moreover, CS1 increased c-maf–targeted cyclin D2-dependent proliferation, -integrin β7/αE-mediated myeloma adhesion to BMSCs, and -vascular endothelial growth factor-induced bone marrow angiogenesis in vivo. These studies provide direct evidence of the role of CS1 in myeloma pathogenesis, define molecular mechanisms regulating its effects, and further support novel therapies targeting CS1 in MM.

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Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma

Blood ◽

10.1182/blood-2004-01-0366 ◽

2005 ◽

Vol 105 (5) ◽

pp. 2132-2134 ◽

Cited By ~ 86

Author(s):

Carmen Choi ◽

Mathias Witzens ◽

Marianna Bucur ◽

Markus Feuerer ◽

Nora Sommerfeldt ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

T Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Hematologic Malignancies ◽

Myeloma Cell ◽

Interferon Γ ◽

Multiple Myeloma Cell ◽

Healthy Donors

AbstractMultiple myeloma (MM) is one of the most common hematologic malignancies. Despite extensive therapeutical approaches, cures remain rare exceptions. An important issue for future immunologic treatments is the characterization of appropriate tumor-associated antigens. Recently, a highly glycosylated mucin MUC1 was detected on a majority of multiple myeloma cell lines. We analyzed bone marrow and peripheral blood of 68 patients with HLA-A2–positive myeloma for the presence and functional activity of CD8 T cells specific for the MUC1-derived peptide LLLLTVLTV. Forty-four percent of the patients with MM contained elevated frequencies of MUC1-specific CD8 T cells in freshly isolated samples from peripheral blood (PB) or bone marrow (BM) compared with corresponding samples from healthy donors. BM-residing T cells possessed a higher functional capacity upon specific reactivation than PB-derived T cells with regard to interferon γ (IFN-γ) secretion, perforin production, and cytotoxicity.

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Lovastatin and Thalidomide Have an Synergic Effect on the Rate of Multiple Myeloma Cell Apoptosis in Short Term Cell Cultures.

Blood ◽

10.1182/blood.v106.11.5121.5121 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5121-5121

Author(s):

Monika Podhorecka ◽

Piotr Klimek ◽

Norbert Grzasko ◽

Anna Dmoszynska

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Cultures ◽

Plasma Cells ◽

Annexin V ◽

Myeloma Cell ◽

Synergic Effect ◽

Treatment Resistant ◽

Short Term ◽

Multiple Myeloma Cell

Abstract Multiple myeloma is characterized by an accumulation of plasma cells in the bone marrow. Despite many therapeutic regimens introduced recently, the prognosis for patients suffering from treatment-resistant or relapsing multiple myeloma is still very poor. Thus, there is an urgent medical need for novel innovative drugs. Thalidomide is successfully used in myeloma patients being reported to induce apoptosis or G1 growth arrest of plasma cells, regulate microvessel density and cytokine secretion. Statins, largely used for the treatment of hypercholesterolemia, seem to be promising drug in multiple myeloma also. High dose of lovastatin has been shown to have antiproliferative effect by inhibition of malignant cell proliferation and inducing programmed cell death. The aim of this study was the assessment of multiple myeloma cells apoptosis induced by mixture of lovastatin and thalidomide in short-term cell cultures. We analyzed plasmocytes of bone marrow samples obtained from 10 patients with treatment-resistant or relapsing multiple myeloma. To assess apoptosis we used Annexin V and propidium iodide binding. We also examined the regulation of BCL-2 and BAX protein expression in the population of CD138+ plasmocytes. The cells were analyzed with use of flow cytometry technique. The experiments were done before and after 72 hours of cell culture. We observed an increase of apoptotic cell number in all cultures supplemented with analyzed drugs in comparison to 0 h culture and to 72 h control. The percentage of Annexin V positive cells in culture with lovastatin and thalidomide mixture was significantly higher in comparison to culture with lovastatin or thalidomide alone (the mean percentages were 33.40 versus 27.04 and 26.49, respectively, p<0.05). The BCL-2/BAX ratio was lower in cell cultures supplemented with mixture of lovastatin and thalidomide (mean ratio 0.95) in comparison to cultures supplemented with lovastatin or thalidomide alone (mean ratio 1.25 and 1.17, p=0.06 and 0.05, respectively) indicating the tendency to apoptosis induction in analyzed cells. Basing on these results we can conclude that lovastatin and thalidomide may have an synergic effect on the rate of multiple myeloma cell apoptosis and may act together on BCL-2 and BAX regulation. Thus, further research should establish both the precise mechanism of this synergic action of statins and thalidomide and the new therapeutic option for myeloma patients.

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

Blood ◽

10.1182/blood-2002-06-1874 ◽

2003 ◽

Vol 101 (2) ◽

pp. 703-705 ◽

Cited By ~ 83

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.

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Transforming Growth Factor β Receptor I Kinase Inhibitor Down-Regulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-04-0632 ◽

2004 ◽

Vol 10 (22) ◽

pp. 7540-7546 ◽

Cited By ~ 74

Author(s):

Toshiaki Hayashi ◽

Teru Hideshima ◽

Aaron N. Nguyen ◽

Olivier Munoz ◽

Klaus Podar ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Growth Factor ◽

Cell Growth ◽

Transforming Growth Factor ◽

Kinase Inhibitor ◽

Transforming Growth Factor Β ◽

Myeloma Cell ◽

Multiple Myeloma Cell ◽

Β Receptor

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Multiple Myeloma Cell Defects Erythropoiesis and Results Anemia Via High Level of CCL3 in Bone Marrow Microenvironment

Blood ◽

10.1182/blood-2020-139006 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 55-55

Author(s):

Lanting Liu ◽

Zhen Yu ◽

Hui Cheng ◽

Weiwei Sui ◽

Shuhui Deng ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Mouse Model ◽

Conflicts Of Interest ◽

Erythroid Differentiation ◽

Myeloma Cell ◽

Cell Infiltration ◽

Prognostic Impact ◽

Multiple Myeloma Cell ◽

Increased Risk

Background: Anemia is the most common complication of myeloma, and is associated with worse clinical outcomes including diminished quality of life, and increased risk of morbidity and mortality. Bone marrow (BM) is the main location of the growth and differentiation of HSPCs. Although marrow replacement by myeloma cell is widely considered a mechanistic rationale for myeloma-related anemia, however the molecular mechanism has not been fully understood. Methods: The clinical characteristics and the prognostic impact of myeloma-related anemia were investigated in patients with multiple myeloma. The erythroid differentiation defects of HSPCs were examined by flow cytometry and colony-formation assay. RNA-seq were conducted to clarify the different gene expression and the signaling pathway in HSPCs. Relative protein levels were determined by immunoblotting and relative gene levels were determined by quantitative real-time PCR. 5TGM1 murine myeloma mouse model was utilized. Results: The data of our large cohort of 1,363 myeloma patients demonstrated that 84.4% of patients had anemia (Hgb<120 g/L), more than 50% of patients had moderate (Hgb=90-120 g/L) or severe anemia (Hgb=60-90 g/L) at the time of diagnosis. Anemia positively correlated with myeloma cell infiltration in the BM and worse outcome of patient. Patient sample and mouse model indicated that the quantity and the erythroid differentiation of HSPCs were affected by myeloma cell infiltration. The number of HPCs was significantly declined in the BM of myeloma, and negatively correlated with the quantity of tumor cells. The master regulator of erythropoiesis GATA1 and KLF1, was obviously down-regulated in myeloma HSPCs cells. However, the gene of chemokine CCL3 was significantly upregulated. Elevated CCL3 in the BM plasma of myeloma further inhibited erythropoiesis of HSPCs through activation of CCL3/CCR1/p38 signaling, and suppressed the expression of GATA1. CCR1 antagonist treatment effectively inhibits CCL3 activity and recovered the expression of GATA1 and rescued the erythropoiesis of HSPCs. Conclusions: myeloma cell infiltration causes the elevation of CCL3 in microenvironment that suppresses the erythropoiesis of HSPCs and results in anemia by downregulating the level of GATA1 of HSPCs. Thus, our study indicates targeting CCL3 would be a potential strategy against anemia and improvement the survival of myeloma patient. Disclosures No relevant conflicts of interest to declare.

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