TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization
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 contri...
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description | 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. |
doi_str_mv | 10.1038/s41375-018-0222-x |
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Jeffrey ; McNiece, Ian ; McCarty, Nami</creator><creatorcontrib>Chen, Zheng ; Lin, Tsung-Chin ; Bi, Xiaohong ; Lu, Guijin ; Dawson, Brian C. ; Miranda, Roberto ; Medeiros, L. Jeffrey ; McNiece, Ian ; McCarty, Nami</creatorcontrib><description>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.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-018-0222-x</identifier><identifier>PMID: 30089913</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/89 ; 38/22 ; 38/23 ; 38/35 ; 42/70 ; 45/77 ; 631/67/1990/804 ; 631/67/71 ; 96/100 ; 96/106 ; 96/2 ; 96/31 ; 96/34 ; 96/44 ; 96/63 ; Animals ; Autografts ; Biocompatibility ; Biomarkers, Tumor ; Cancer ; Cancer Research ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Cycle ; Cell Proliferation ; Cell survival ; Cells, Cultured ; Chemotherapy ; Critical Care Medicine ; Fluorescence ; Fluorescent indicators ; Hematology ; Heterogeneity ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Intensive ; Internal Medicine ; Intracellular Signaling Peptides and Proteins ; Medicine ; Medicine & Public Health ; Mice, Inbred NOD ; Mice, SCID ; Multiple myeloma ; Multiple Myeloma - genetics ; Multiple Myeloma - metabolism ; Multiple Myeloma - pathology ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Occupancy ; Oncology ; Osteoblasts ; Osteoblasts - metabolism ; Osteoblasts - pathology ; Patients ; Protein Stability ; Proteins ; Signal Transduction ; Stem cell transplantation ; Stem cells ; Survival ; Tracers ; Transplantation ; Tripartite Motif Proteins ; Ubiquitination ; Xenograft Model Antitumor Assays ; Xenografts ; Xenotransplantation</subject><ispartof>Leukemia, 2019-02, Vol.33 (2), p.469-486</ispartof><rights>The Author(s) 2018</rights><rights>2018. 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Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-125024af1d4dab4821ee00d8a4281a06f105030783004d859df841be9c8f65a73</citedby><cites>FETCH-LOGICAL-c470t-125024af1d4dab4821ee00d8a4281a06f105030783004d859df841be9c8f65a73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41375-018-0222-x$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41375-018-0222-x$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30089913$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Zheng</creatorcontrib><creatorcontrib>Lin, Tsung-Chin</creatorcontrib><creatorcontrib>Bi, Xiaohong</creatorcontrib><creatorcontrib>Lu, Guijin</creatorcontrib><creatorcontrib>Dawson, Brian C.</creatorcontrib><creatorcontrib>Miranda, Roberto</creatorcontrib><creatorcontrib>Medeiros, L. Jeffrey</creatorcontrib><creatorcontrib>McNiece, Ian</creatorcontrib><creatorcontrib>McCarty, Nami</creatorcontrib><title>TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>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.</description><subject>13/1</subject><subject>13/89</subject><subject>38/22</subject><subject>38/23</subject><subject>38/35</subject><subject>42/70</subject><subject>45/77</subject><subject>631/67/1990/804</subject><subject>631/67/71</subject><subject>96/100</subject><subject>96/106</subject><subject>96/2</subject><subject>96/31</subject><subject>96/34</subject><subject>96/44</subject><subject>96/63</subject><subject>Animals</subject><subject>Autografts</subject><subject>Biocompatibility</subject><subject>Biomarkers, Tumor</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Cycle</subject><subject>Cell Proliferation</subject><subject>Cell survival</subject><subject>Cells, Cultured</subject><subject>Chemotherapy</subject><subject>Critical Care Medicine</subject><subject>Fluorescence</subject><subject>Fluorescent indicators</subject><subject>Hematology</subject><subject>Heterogeneity</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - chemistry</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Multiple myeloma</subject><subject>Multiple Myeloma - genetics</subject><subject>Multiple Myeloma - metabolism</subject><subject>Multiple Myeloma - pathology</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Occupancy</subject><subject>Oncology</subject><subject>Osteoblasts</subject><subject>Osteoblasts - metabolism</subject><subject>Osteoblasts - pathology</subject><subject>Patients</subject><subject>Protein Stability</subject><subject>Proteins</subject><subject>Signal Transduction</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Survival</subject><subject>Tracers</subject><subject>Transplantation</subject><subject>Tripartite Motif Proteins</subject><subject>Ubiquitination</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kd9qFDEYxYModl19AG8k4I03o18ySSZ7I0ix7UJFkHodMplMm5JJppPM0u1b-SI-UzNsrX_Aq0DO7zv5Tg5Crwm8J1DLD4mRuuEVEFkBpbS6fYJWhDWi4pyTp2gFUjaV2FB2hF6kdA2wiOI5OqoB5GZD6hW6u_i2_cIYHqc4xGwTvpmdTcaGjIfZZzd6i4e99XHQ2FjvcTRmHnUwe6xDh9M87dxOe-wCzlcWx5RtbL1O2RkcnClXO6fx2fakIj9_4JR167y709nF8BI967VP9tXDuUbfTz5fHJ9V519Pt8efzivDGsgVoRwo0z3pWKdbJimxFqCTmlFJNIieAIcaGllCsU7yTddLRlq7MbIXXDf1Gn08-I5zO9huyTZpr8bJDXraq6id-lsJ7kpdxp0SteC1rIvBuweDKd7MNmU1uLR8hg42zklRkIIKRgq9Rm__Qa_jPIUST1HSiAYkp7JQ5ECZKaY02f5xGQJqaVYdmlWlWbU0q27LzJs_UzxO_KqyAPQApCKFSzv9fvr_rvc6urD2</recordid><startdate>20190201</startdate><enddate>20190201</enddate><creator>Chen, Zheng</creator><creator>Lin, Tsung-Chin</creator><creator>Bi, Xiaohong</creator><creator>Lu, Guijin</creator><creator>Dawson, Brian C.</creator><creator>Miranda, Roberto</creator><creator>Medeiros, L. 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Jeffrey ; McNiece, Ian ; McCarty, Nami</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-125024af1d4dab4821ee00d8a4281a06f105030783004d859df841be9c8f65a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/1</topic><topic>13/89</topic><topic>38/22</topic><topic>38/23</topic><topic>38/35</topic><topic>42/70</topic><topic>45/77</topic><topic>631/67/1990/804</topic><topic>631/67/71</topic><topic>96/100</topic><topic>96/106</topic><topic>96/2</topic><topic>96/31</topic><topic>96/34</topic><topic>96/44</topic><topic>96/63</topic><topic>Animals</topic><topic>Autografts</topic><topic>Biocompatibility</topic><topic>Biomarkers, Tumor</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Cycle</topic><topic>Cell Proliferation</topic><topic>Cell survival</topic><topic>Cells, Cultured</topic><topic>Chemotherapy</topic><topic>Critical Care Medicine</topic><topic>Fluorescence</topic><topic>Fluorescent indicators</topic><topic>Hematology</topic><topic>Heterogeneity</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - chemistry</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Multiple myeloma</topic><topic>Multiple Myeloma - genetics</topic><topic>Multiple Myeloma - metabolism</topic><topic>Multiple Myeloma - pathology</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Occupancy</topic><topic>Oncology</topic><topic>Osteoblasts</topic><topic>Osteoblasts - metabolism</topic><topic>Osteoblasts - pathology</topic><topic>Patients</topic><topic>Protein Stability</topic><topic>Proteins</topic><topic>Signal Transduction</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Survival</topic><topic>Tracers</topic><topic>Transplantation</topic><topic>Tripartite Motif Proteins</topic><topic>Ubiquitination</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Zheng</creatorcontrib><creatorcontrib>Lin, Tsung-Chin</creatorcontrib><creatorcontrib>Bi, Xiaohong</creatorcontrib><creatorcontrib>Lu, Guijin</creatorcontrib><creatorcontrib>Dawson, Brian C.</creatorcontrib><creatorcontrib>Miranda, Roberto</creatorcontrib><creatorcontrib>Medeiros, L. 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Jeffrey</au><au>McNiece, Ian</au><au>McCarty, Nami</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2019-02-01</date><risdate>2019</risdate><volume>33</volume><issue>2</issue><spage>469</spage><epage>486</epage><pages>469-486</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30089913</pmid><doi>10.1038/s41375-018-0222-x</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 13/1 13/89 38/22 38/23 38/35 42/70 45/77 631/67/1990/804 631/67/71 96/100 96/106 96/2 96/31 96/34 96/44 96/63 Animals Autografts Biocompatibility Biomarkers, Tumor Cancer Cancer Research Carrier Proteins - genetics Carrier Proteins - metabolism Cell Cycle Cell Proliferation Cell survival Cells, Cultured Chemotherapy Critical Care Medicine Fluorescence Fluorescent indicators Hematology Heterogeneity Humans Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit - chemistry Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Intensive Internal Medicine Intracellular Signaling Peptides and Proteins Medicine Medicine & Public Health Mice, Inbred NOD Mice, SCID Multiple myeloma Multiple Myeloma - genetics Multiple Myeloma - metabolism Multiple Myeloma - pathology Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Occupancy Oncology Osteoblasts Osteoblasts - metabolism Osteoblasts - pathology Patients Protein Stability Proteins Signal Transduction Stem cell transplantation Stem cells Survival Tracers Transplantation Tripartite Motif Proteins Ubiquitination Xenograft Model Antitumor Assays Xenografts Xenotransplantation |
title | TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization |
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