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Identifying a high-risk cellular signature in the multiple myeloma bone marrow microenvironment

ABSTRACT: Identifying a high-risk cellular signature in the multiple myeloma bone marrow microenvironment

PROVIDER: PRJNA563125 | ENA |

REPOSITORIES: ENA

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Identifying a high-risk cellular signature in the multiple myeloma bone marrow microenvironment_1

Project description:The multiple myeloma (MM) tumor microenvironment is thought to influence patient outcomes. To test this, we computationally enumerated relevant cell populations in 436 newly diagnosed MM patients. Unsupervised clustering identified 5 clusters, with patients in Cluster 5 having significantly worse outcomes: 13 fewer months of progression-free survival (P = 0.002) and 8 fewer months of overall survival (P = 0.040). Cell type analysis showed that patients in Cluster 5 had elevated CD8+ T cell and B cell populations, but low granulocyte levels. A granulocyte signature identified an additional 14% of patients with elevated risk but lacking International Staging System stage III or GEP-70 high- risk status

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Identifying a high-risk cellular signature in the multiple myeloma bone marrow microenvironment_3

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Identifying a high-risk cellular signature in the multiple myeloma bone marrow microenvironment_1

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Identifying a high-risk cellular signature in the multiple myeloma bone marrow microenvironment

Project description:This SuperSeries is composed of the SubSeries listed below.

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Multiple myeloma-derived extracellular vesicles modulate the bone marrow immune microenvironment

Project description:One of the hallmarks of multiple myeloma (MM) is a permissive BM microenvironment. Increasing evidence suggest that cell-to-cell communication between myeloma and immune cells via tumor cell-derived extracellular vesicles (EV) plays a key role in the pathogenesis of MM. Hence, we aimed to explore BM immune alterations induced by MM-derived EV. For this, we inoculated immunocompetent BALB/cByJ mice with a myeloma cell line - MOPC315.BM -, inducing a MM phenotype. Upon tumor establishment, characterization of the BM microenvironment revealed the expression of both activation and suppressive markers by lymphocytes, such as Granzyme b and PD-1, respectively. In addition, conditioning of the animals with MOPC315.BM-derived EV, before transplantation of the MOPC315.BM tumor cells, did not anticipate the disease phenotype. However, it induced features of suppression in the BM milieu, such as an increase in PD-1 expression by CD4+ T cells. Overall, our findings reveal the involvement of MOPC315.BM-derived EV protein content as promoters of immune niche remodeling, strengthening the importance of assessing the mechanisms by which MM may impact the immune microenvironment.

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Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment

Project description:The myeloma bone marrow microenvironment drives proliferation of malignant plasma cells and promotes resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells.Here, we validated both in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not rescue ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells drive a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.

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Transcriptomic analysis of Multiple Myeloma bone marrow microenvironment

Project description:Transcriptomic analysis of Multiple Myeloma bone marrow microenvironment

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