Abstract
Multiple myeloma (MM) is an aggressive malignancy characterized by terminally differentiated plasma cells accumulation in the bone marrow (BM). MM BM exhibits elevated MΦs (macrophages) numbers relative to healthy BM. Current evidence indicates that MM-MΦs (MM-associated macrophages) have pro-myeloma functions, and BM MM-MΦs numbers negatively correlate with patient survival. Here, we found that BMI1, a polycomb-group protein, modulates the pro-myeloma functions of MM-MΦs, which expressed higher BMI1 levels relative to normal MΦs. In the MM tumor microenvironment, hedgehog signaling in MΦs was activated by MM-derived sonic hedgehog, and BMI1 transcription subsequently activated by c-Myc. Relative to wild-type MM-MΦs, BMI1-KO (BMI1 knockout) MM-MΦs from BM cells of BMI1-KO mice exhibited reduced proliferation and suppressed expression of angiogenic factors. Additionally, BMI1-KO MM-MΦs lost their ability to protect MM cells from chemotherapy-induced cell death. In vivo analysis showed that relative to wild-type MM-MΦs, BMI1-KO MM-MΦs lost their pro-myeloma effects. Together, our data show that BMI1 mediates the pro-myeloma functions of MM-MΦs.
Highlights
Multiple myeloma (MM) is an incurable malignancy characterized by accumulation of terminally differentiated plasma cells in the bone marrow (BM)
Characterization of MM-MΦs in a murine myeloma model To investigate the interplay between MΦ and MM cells, we used the 5 T murine myeloma model[5,15]
These MM-MΦ features were used as readouts in downstream analyses aiming to elucidate the molecular factors modulating MM-MΦs
Summary
Multiple myeloma (MM) is an incurable malignancy characterized by accumulation of terminally differentiated plasma cells in the bone marrow (BM). The close interaction between MM cells and the BM microenvironment is essential for MM development, progression and prognosis[1,2]. Macrophages (MΦs) are important and abundant cellular components of MM BM microenvironment. In which tumor associated macrophages (TAMs) are “educated” by the tumor microenvironment to acquire cancer promoting functions[3,4], MM-associated macrophages (MM-MΦs) are influenced. Official journal of the Cell Death Differentiation Association. Zhang et al Cell Death and Disease (2021)12:495
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