Abstract
Despite progress in the treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients are refractory to all therapies. This resistance is related to the molecular genetic heterogeneity in MM cells as well as to the contributions from the BM, which is one of the key determinants of treatment outcome. Our previous studies using fluorescent tracers revealed that MM heterogeneity is correlated with the presence of quiescent stem-like cancer cells, which prefer to reside within the osteoblastic niche of the BM. In this report, we identified a novel protein, tripartite motif containing 44 (TRIM44), which is overexpressed in the osteoblastic niche of the BM, enabling MM cells to compete with HSCs for niche support. TRIM44 expression in MM cells promoted cell quiescence but increased bone destruction in xenograft mice, similar to what is observed in MM patients. TRIM44 functions as a deubiquitinase for hypoxia inducible factor-1α (HIF-1α), which stabilizes HIF-1α expression during hypoxia and normoxia. Stabilized HIF-1α stimulates MM cell growth and survival during hypoxia. Our work is the first report to reveal signaling in quiescent MM cells and the functions of TRIM44.
Highlights
MM cells and human hematopoietic stem cells (HSCs) occupy the same niche within the bone marrow (BM)
Symptomatic MM is a gradual progression from MGUS or smoldering multiple myeloma (SMM), and the progression is pathologically determined based on the decreased proportion of normal plasma cells within the BM plasma cells [17]
During a short-term incubation, the recovery rates of CD34+ HSCs after 60 h were decreased in proportion to the increased numbers of MM cells injected in all three MM cell lines (Fig. 1a, Table S1, top), and their R2 values show an inverse correlation (Fig. 1a, Table S1, bottom)
Summary
Despite progress in the treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients are refractory to all therapies [1]. This resistance is related to the molecular genetic heterogeneity in the MM cells, as well as to the contributions of the BM, which is one of the key determinants of treatment outcome. Rare quiescent PKH+ cells preferentially reside within osteoblastic (OS) niches rather than in vascular (VS) niches of the BM or spleens Functional analyses of these cells revealed enhanced colony forming properties in vitro. These PKH+ stem-like cells were highly tumorigenic upon serial transplantation and were resistant to a variety of clinically relevant chemotherapeutic drugs [2]
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