Signaling

Defines the hierarchical IRF4 to BLIMP1 transcriptional cascade in human plasma cell differentiation, with IRF4 acting upstream via ISRE/EICE motifs.

Single-cell RNAseq of the bone marrow niche reveals IL-6/JAK-STAT3 as the central immunometabolic hub linking malignant plasma cells, macrophages, and exhausted T cells.

IL-6/JAK/STAT3 activates the B-cell transcription factors POU2AF1 and ELL2 as myeloma-specific survival targets downstream of the cytokine axis.

Broad review placing myeloma's dual canonical/non-canonical NF-kB activation in context of oncogenic mutations and stromal signals.

Transcriptomic screen uncovers RIDD substrates that regulate myeloma survival independent of the XBP1 splicing branch.

Bidirectional NF-kB signaling between myeloma cells and bone marrow mesenchymal stromal cells reinforces tumor survival and drug resistance.

Non-canonical NF-kB/NIK/p52 arm reviewed as a distinct and druggable survival pathway in myeloma, separate from the classical p65 pathway.

Reviews how CXCL12, APRIL, BAFF, and adhesion molecules collectively define the long-lived plasma cell survival niche in bone marrow.

APRIL to BCMA to PI3K and NF-kB jointly suppress mitochondrial apoptosis and ER stress in bone marrow plasma cells.

Comprehensive review of CXCR4/CXCL12 axis functions in myeloma: bone marrow homing, retention, extramedullary disease, and drug resistance.

Canonical review establishing that approximately 85% of myeloma cases harbor activating mutations in the canonical or non-canonical NF-kB pathway.

BLIMP1 as master repressor of B cell identity genes while activating the secretory machinery and UPR program during plasmablast transition.

Classic paper establishing that SDF-1/CXCL12 drives myeloma cell migration, bone marrow adhesion, and protection from apoptosis via CXCR4.

Canonical paper establishing that IRE1-driven XBP1 splicing is essential for plasma cell differentiation and immunoglobulin secretory capacity.

TACI receptor signaling suppresses mitochondrial reactive oxygen species; its loss causes plasma cell death, identifying a key cell-intrinsic survival mechanism in the bone marrow niche.

Single-cell multiomic analysis identified two distinct plasma cell differentiation routes in humans, differing by RGS13 expression and surface markers CD10, CD31, CD38, and CD44.

Pooled in vivo CRISPR screen in the splenic microenvironment uncovered novel genetic regulators governing the transition from activated B cells to plasmablasts.

Approximately 1 in 100 memory B cells differentiates into an antibody-secreting plasmablast per year, quantifying steady-state plasmablast output in healthy humans (PNAS 2026).

RUNX1 acts as a stage-specific transcription factor during plasma cell differentiation and is deregulated in myeloma pathogenesis.

Nonsense-mediated mRNA decay rises at B cell activation and stays high in antibody-secreting cells; limited PERK-eIF2a activation preserves it. Upf1 knockdown severely compromised viability. Mouse.

B cell-specific Ptpn2 knockout: loss hyperactivates Lyn, STAT1, STAT3, increasing plasma cell differentiation and antiviral titers without loss of affinity. Mouse.

hnRNPK deletion causes excess plasma cell and memory precursor differentiation; acts via Hhex, Zfp318 and a glycolysis-CD25 axis; IL-2/CD25 blockade rescues. Mouse.

Review: long-lived plasma cells rely on BCMA, TACI, and CD28 receptor signals to upregulate anti-apoptotic factors; multiple metabolic pathways are also upregulated for survival in the marrow niche.

Pulse-labelling approach (timestamping) shows longevity is not a fixed fate but depends on isotype (IgA vs IgG) and tissue context (spleen vs bone marrow). Mouse.

IL-6 drives glycolytic and glutamine-metabolic programs in malignant plasma cells; single-cell profiling maps the immunometabolic crosstalk between myeloma plasmocytes and the marrow microenvironment.

48 MM patients and 10 controls: IFN-gamma, IL-10, and MCP-1 elevated in MM; IL-17A and TGF-alpha reduced. Active disease correlates with higher IL-10 and TNF-alpha. Extramedullary disease carries a distinct inflammatory signature with further elevation of IFN-gamma, IL-10, and MCP-1. IL-6, IL-10, IL-9, IL-17A, and TGF-alpha associate with PFS. The neuropeptide PACAP-38 correlates positively with IL-10 and negatively with MCP-1. Small cohort; larger validation needed.

Human bone marrow-on-a-chip with perfusable endosteal and perivascular compartments. Human ASCs migrate through blood vessels and accumulate in perivascular areas enriched for survival factors. The endosteal niche independently affects ASC survival, movement, and retention. A subset of ASCs shows stop-and-go migration partially driven by CXCR4-CXCL12 signaling. First direct mechanistic look at which human BM subniche does what for plasmocyte longevity, in human cells rather than mouse models.

Live imaging in mouse BM. Plasma cells alternate between high-motility and arrested phases; arrested cells accumulate in clusters with reduced motility. CXCL12-CXCR4 drives motility; CXCR4 expression rises with plasma cell maturation rather than host age. Clusters are enriched for long-lived plasma cells, suggesting they mark survival niches. No concentration ranges given for CXCL12 or IL-6 in the niche; dynamics are measured, not signal levels.

Human BM plasma cells die within days in isolation; co-culture with BM stromal cells rescues them. Survival requires PI3K and canonical NF-kappaB signaling, but is independent of exogenous APRIL and BAFF alone. Soluble stromal factors not yet fully identified. First human in vitro dissection of stromal dependency separate from APRIL/BAFF.

Mouse in vivo. CD138 (syndecan-1) binds APRIL; CD138-high plasma cells outcompete CD138-low newcomers for niche occupancy. Acute TACI-Fc blockade (neutralising APRIL and BAFF together) disrupts clusters and mobilises plasma cells within hours, demonstrating that APRIL is continuously required for cluster retention. CD138 level sets competitive fitness, not only a surface marker. Directly relevant to niche slider: APRIL is the signal sustaining the niche, cluster retention is the measurable output.

Preprint. Allograft rejection context, not normal bone marrow. IL-6 trans-signaling (soluble IL-6R plus IL-6) drives CXCL12 expression in MSCs and establishes ectopic plasma cell niches in rejecting lungs. Demonstrates that IL-6 and CXCL12 are coupled in the niche microenvironment; the interaction may be relevant to normal BM but the concentrations here are from a disease model.

Research highlight. Intermittent fasting impairs humoral immunological memory by beta-hydroxybutyrate-mediated depletion of long-lived plasma cells from the bone marrow niche. Demonstrates that active niche occupancy is required continuously: disrupting the survival signals (not just blocking entry) removes established LLPCs within the fasting window. Relevant to niche slider: the niche is not static storage but an active maintenance requirement. Secondary (news piece); primary paper should be tracked separately if PMID becomes available.

Mouse and human. Gut lamina propria plasma cells secrete less IgA per cell than bone marrow plasma cells; restriction is driven by a glycolytic program specific to the mucosal tissue microenvironment. Identifies LDHA and tissue lactate as the metabolic brake. Relevant to the glucose import withheld entry: this paper links glycolytic flux directly to Ig secretion rate, confirming that glucose import is a rate-limiting input. Still insufficient for a per-cell glucose import rate in molecules per second; withheld entry stands.

Human. Identifies the cell types and soluble factors in the BM microniche that sustain human plasma cell survival: megakaryocyte-derived APRIL, eosinophil IL-6, stromal CXCL12, and direct cell contact. Measures IL-6 and APRIL concentration ranges used in BM mimetic cultures to sustain plasma cells in vitro. This paper is the upstream source for the 2025 Nguyen DC BM mimetic culture system (PMID 40963623). Directly relevant to line 14 niche slider: IL-6 concentrations used in survival assays are quantified here. Adding as candidate source for the niche slider pending a read of the measured ranges with species and method.

Mouse. Quantifies how many plasma cells the bone marrow survival niche can sustain and how competitive exclusion operates when new plasma cells arrive. Relevant to the niche slider: carrying capacity and competitive dynamics shape which plasma cells survive long-term; this is the mechanism behind CD138-mediated competition (Park 2025, PMID 40768334) expressed as a number. Mouse data; human carrying capacity is not given.