APRIL promotes cell-cycle progression in primary multiple myeloma cells: influence of D-type cyclin group and translocation status

Quinn, John A.; Glassford, Janet; Percy, Laura; Munson, Philippa; Marafioti, Teresa; Rodriguez‐Justo, Manuel; Yong, Kwee

doi:10.1182/blood-2010-01-264424

Cited by 50 publications

(51 citation statements)

References 42 publications

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“…By contrast, we detected secreted APRIL on some MM tumor cells (Figure 5c, lower panel). Notably, secreted APRIL was clearly present in the cytoplasm of MM cells, confirming a previous analysis performed with the same Aprily-2 mAb, 19 and implying an internalization of secreted APRIL by tumor cells. Taken together, our data show that MM cells infiltrating BM express HS chains on CD138 able to bind soluble APRIL.…”

Section: In Vivosupporting

confidence: 74%

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Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow

Matthes

Mckee²,

Dunand-Sauthier³

et al. 2015

Leukemia

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Multiple myeloma (MM) is a non-curable tumor developing in the bone marrow (BM). The BM microenvironment rich in hematopoietic precursors is suspected to have a role in MM development. Here we show that a proliferation-inducing ligand (APRIL) mediated in vivo MM promotion. In MM-infiltrated BM, APRIL originated from differentiating myeloid cells with an expression peak in precursor cells. Notably, APRIL expression stayed stable in BM despite MM infiltration. The pool of APRIL-producing cells changed upon MM infiltration. Although CD16(+) mature myeloid cells constituted about half of the APRIL-producing cells in healthy BM, CD16(-) Elastase(+) myeloid precursor cells were predominant in MM-infiltrated BM. Myeloid precursor cells secreted all the APRIL they produced, and binding of secreted APRIL to MM cells, strictly dependent of heparan sulfate carried by CD138, resulted in an in situ internalization by tumor cells. This indicated APRIL consumption by MM in BM. Taken together, our data show that myelopoiesis dysregulation characterized by an increased proportion of precursor cells occurs in MM patients. Such dysregulation correlates with a stable expression of the MM-promoting factor APRIL in infiltrated BM

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Section: In Vivosupporting

confidence: 74%

“…In MM, APRIL increases cell cycle progression and survival. [17][18][19] In a mouse preclinical model, a soluble form of TACI reduces tumor development in fetal bones implanted into immunodeficient mice.…”

Section: Introductionmentioning

confidence: 99%

Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow

Matthes

Mckee²,

Dunand-Sauthier³

et al. 2015

Leukemia

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show abstract

“…13,14 BCMA is expressed on MM cell lines and malignant plasma cells with high prevalence and increased expression levels during disease progression from monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma to active MM. [15][16][17][18][19][20][21] BCMA is also expressed on plasmacytoid dendritic cells, which promote MM cell growth, survival and drug resistance. [21][22][23] Expression levels on plasmacytoid dendritic cells are also elevated in MM patients versus normal donors.…”

Section: Introductionmentioning

confidence: 99%

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

et al. 2016

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B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ε (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMApositive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/ refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

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“…20,21,25,[29][30][31] APRIL can rescue interleukin 6 (IL-6)-dependent MM cell lines from apoptosis following IL-6 deprivation, 18,22,32 and stimulate MM cell growth via cyclin D-dependent G1/S cell cycle progression. 33 Taken together, these results suggest a potential treatment strategy using a blocking anti-APRIL mAb to prevent BCMA activation in MM.…”

Section: Introductionmentioning

confidence: 93%

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

Tai

Acharya

et al. 2016

Blood

277

242

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Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM

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APRIL promotes cell-cycle progression in primary multiple myeloma cells: influence of D-type cyclin group and translocation status

Cited by 50 publications

References 42 publications

Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow

Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

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