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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Veröffentlicht in:Leukemia 2019-02, Vol.33 (2), p.469-486
Hauptverfasser: Chen, Zheng, Lin, Tsung-Chin, Bi, Xiaohong, Lu, Guijin, Dawson, Brian C., Miranda, Roberto, Medeiros, L. Jeffrey, McNiece, Ian, McCarty, Nami
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container_end_page 486
container_issue 2
container_start_page 469
container_title Leukemia
container_volume 33
creator Chen, Zheng
Lin, Tsung-Chin
Bi, Xiaohong
Lu, Guijin
Dawson, Brian C.
Miranda, Roberto
Medeiros, L. Jeffrey
McNiece, Ian
McCarty, Nami
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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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. 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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. 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subjects 13/1
13/89
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38/23
38/35
42/70
45/77
631/67/1990/804
631/67/71
96/100
96/106
96/2
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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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