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

Abstract

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

Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma

“…However, in our study some intermediate time points included a relatively small number of animals (N=4) and need confirmation in future studies. In the MOPC315.BM model, a strong downregulation of all hematopoietic precursor cells except those from myeloid lineage was reported early upon MM infiltration in the BM [21]. Thus, we can not exclude that the observed increases in MDSC percentages are partially caused by a reduction in total BM cells.…”

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

“…18 Our data further show that APRIL binds to BCMA in TACI low/neg cells (ie, H929, U266, and INA6) and induces protection against lenalidomideinduced apoptosis, indicating that paracrine APRIL promotes MM growth and survival in the BM. 25,62 01A, which completely blocks all APRIL-induced target genes in MM cells, significantly inhibits baseline cell proliferation and completely abolishes APRIL-induced U266 (p53 mut ) cell growth and drug resistance. Further, APRIL induces MM cell adherence to bone marrow stromal cells (BMSCs) and drug resistance, which is abrogated by 01A.…”

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

“…42,43 These myeloid precursor cells may have the capacity to differentiate into OCPs in the presence of RANKL. OCPs give rise to macrophages, DCs, and OCs depending upon the presence of cytokines and growth factors.…”