Elucidating altered transcriptional programs

In addition, these studies indicated that myeloma cells are not statically confined to the bone marrow.

Multiple myeloma is an exclusively bone marrow–localized malignancy generating from normal plasma cell differentiation.

Plasma cell maturation involves migration of pre-germinal center (GC) B cells from the bone marrow to secondary lymphoid organs and return to the bone marrow as mature plasma cells.

) to relatively normoxic sites of bone marrow via CXCR4 (see figure).

Hypothesized mechanism of role of hypoxia in the dissemination of MM.

Post-GC homing is mediated by CXCR4-induced homing to CXCL12/SDF-1–rich regions of bone marrow niche.

Within the bone marrow plasma cell adherence to ECM, bone marrow stromal cells (BMSCs) and other juxtaposed cells lead to the production of crucial factors for bone marrow homeostasis.

Unlike their normal counterparts, myeloma cells benefit from the normal effectors within the bone marrow niche, and also hijack and contribute to the environment promoting tumorigenesis, altered bone metabolism, neovascularization, drug resistance, and as now shown, myeloma metastasis.

The effect of reduced tissue oxygen is primarily mediated by hypoxia inducible factors (HIFs), a family of heterodimeric basic helix-loop-helix transcription factors consisting of an oxygen sensitive α subunit (HIF-1α, HIF-2α, and HIF-3α) and a constitutively expressed β subunit (HIFβ).

To date, this has been the exclusive domain of embryonic development, response to injury, and solid-tumor cancer metastasis.

The results suggest that myeloma cells (and potentially all tumor cells) are subject to differentiation (or de-differentiation) programs induced by the tumor microenvironment.

In multiple myeloma the bone marrow microenvironment promotes proliferation and resistance to chemotherapy.

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