TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization
| Autor: | Nami McCarty, L. Jeffrey Medeiros, Xiaohong Bi, Brian Dawson, Ian K. McNiece, Zheng Chen, Tsung-Chin Lin, Guijin Lu, Roberto N. Miranda |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Mice SCID Article Tripartite Motif Proteins 03 medical and health sciences 0302 clinical medicine Autologous stem-cell transplantation Cell quiescence Mice Inbred NOD Biomarkers Tumor medicine Animals Humans Hypoxia Cells Cultured Multiple myeloma Cell Proliferation Osteoblasts Protein Stability Chemistry Cell growth Cell Cycle Intracellular Signaling Peptides and Proteins Ubiquitination Hematology Cell cycle Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Xenograft Model Antitumor Assays 3. Good health 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer cell Neoplastic Stem Cells Cancer research Signal transduction Carrier Proteins Multiple Myeloma Signal Transduction |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/s41375-018-0222-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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