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

Matthes, Thomas; Mckee, Thomas Alexander; Dunand-Sauthier, Isabelle; Manfroi, Benoît; Park, S; Passweg, Jakob; Huard, Bertrand

doi:10.1038/leu.2015.68

Cited by 19 publications

(20 citation statements)

References 44 publications

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“…APRIL pattern of expression did not change upon BM infiltration by MM with myeloid precursor cells remaining the main source. 2 This latter observation is consistent, at least in part, with the strong dependency of MM cells on their microenvironment. 6 However, it also implies that MM cells may also limit their development by displacing APRIL-producing cells in BM.…”

Section: Introductionsupporting

confidence: 63%

“…APRIL mRNA upregulation was more than twofold in immature cells compared with mature cells, very similar to the differences already reported in healthy mouse BM, 4 and comparable to human MM. 2 Taken together, these results indicate that Gr-1 low cells resisting MM infiltration were bona fide myeloid precursor cells. These experiments demonstrate that MM cells strongly decrease all hematopoietic precursors upon BM infiltration with the exception of high APRIL-producing myeloid precursor cells.…”

Section: Highmentioning

confidence: 77%

“…1 APRIL is also implicated in the development of multiple myeloma (MM), a tumor originating from plasma cells developing in bone marrow (BM). 2,3 We recently reported that most of the APRIL production in healthy BM originates from a specific hematopoietic lineage, the myeloid cells. 4 Myelopoiesis is an extremely active hematopoietic process, as a human adult produces more than 10 11 mature myeloid cells per day.…”

Section: Introductionmentioning

confidence: 99%

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Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow

Matthes

Manfroi

Zeller³

et al. 2015

Leukemia

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Multiple myeloma (MM) invariably develops in the bone marrow (BM), indicating the strong requirement of this tumor for the peculiar BM microenvironment, rich in cytokine and hematopoietic precursor cells. Interleukin-6 (IL-6) and a proliferation inducing ligand (APRIL) are key cytokines implicated in MM development. Here, we show that MM cells changed the hematopoietic microenvironment early upon BM infiltration by strongly downregulating hematopoietic precursor cells from all lineages except myeloid precursor cells. Myeloid precursor cells constituted a major source of APRIL in MM-infiltrated BM, and their proliferative response to IL-6 upregulation explained their relative resistance to MM infiltration. The osteolytic molecule receptor activator of NF-kB ligand (RANK-L) expressed by MM cells started this myeloid proliferation by inducing in a contact-dependent manner IL-6 production by myeloid precursor cells themselves. Taken together, our data demonstrate that MM cells do not simply displace hematopoietic cells upon BM infiltration, but rather selectively modulate the BM microenvironment to preserve a pool of high APRIL-producing myeloid precursor cells. Our data also identify a positive regulation of APRIL by IL-6 in myeloid precursor cells

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Section: Introductionsupporting

confidence: 63%

Section: Highmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow

Matthes

Manfroi

Zeller³

et al. 2015

Leukemia

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“…23,[26][27][28] In addition to receptormediated effects and in contrast to BAFF, APRIL can promote the survival of malignant PCs directly through heparan sulfate proteoglycans, ie, CD138, which regulate growth factor signaling, cytoskeleton organization, cell adhesion, and migration. 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: 99%

“…7,22,23 APRIL is primarily secreted by myeloid cells and sustained during abnormal myelopoiesis in MM-infiltrated BM. 24,25 In ex vivo cultures, osteoclasts (OCs), which stimulate MM growth and bone lesions during disease progression, produce more APRIL than CD14 1 unstimulated monocytes. 23,[26][27][28] In addition to receptormediated effects and in contrast to BAFF, APRIL can promote the survival of malignant PCs directly through heparan sulfate proteoglycans, ie, CD138, which regulate growth factor signaling, cytoskeleton organization, cell adhesion, and migration.…”

Section: Introductionmentioning

confidence: 99%

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

Tai

Acharya

et al. 2016

Blood

263

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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A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis

Baert

Benkhoucha

Popa

et al. 2019

Annals of Neurology

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Objective The two related tumor necrosis factor members a proliferation‐inducing ligand (APRIL) and B‐cell activation factor (BAFF) are currently targeted in autoimmune diseases as B‐cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS. Methods APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes. Results APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL‐10 to dampen antigen‐specific T‐cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect. Interpretation Our data show that APRIL mediates an anti‐inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406–420.

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

Cited by 19 publications

References 44 publications

Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow

Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow

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

A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis

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