TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization.
TRIM44 promotes quiescent multiple myeloma cell occupancy and survival in the osteoblastic niche via HIF-1α stabilization.
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DOI：
10.1038/s41375-018-0222-x
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发表时间：
2019-03
期刊：
影响因子：
11.4
通讯作者：
McCarty N
中科院分区：
文献类型：
--
作者：
Chen Z;Lin TC;Bi X;Lu G;Dawson BC;Miranda R;Medeiros LJ;McNiece I;McCarty N
尽管MM的治疗取得了进展，包括使用高剂量化疗和自体干细胞移植，但相当一部分患者对所有治疗方法都难以治愈。这种耐药性与MM细胞的分子遗传异质性以及BM的贡献有关，这是治疗结果的关键决定因素之一。我们之前使用荧光示踪剂的研究表明，MM的异质性与静态干细胞样癌细胞的存在有关，这些癌细胞更倾向于居住在BM的成骨细胞生态位中。在这篇报道中，我们发现了一种新的蛋白，tripartite motif containing 44 (TRIM44)，它在BM的成骨细胞生态位中过表达，使MM细胞能够与hsc竞争生态位支持。TRIM44在MM细胞中的表达促进了异种移植小鼠的细胞静止，但增加了骨破坏，与在MM患者中观察到的情况相似。TRIM44作为缺氧诱导因子-1α (HIF-1α)的去泛素酶，在缺氧和常氧条件下稳定HIF-1α的表达。稳定的HIF-1α刺激缺氧时MM细胞的生长和存活。我们的研究首次揭示了静止MM细胞中的信号传导和TRIM44的功能。
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.
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影响因子：
20.3
作者：
Forristal, Catherine E.;Winkler, Ingrid G.;Levesque, Jean-Pierre
通讯作者：
Levesque, Jean-Pierre
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
20.3
作者：
Matsui, W;Huff, CA;Jones, RJ
通讯作者：
Jones, RJ
DOI：
10.1158/1078-0432.ccr-12-1881
发表时间：
2013-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Munshi NC;Anderson KC
通讯作者：
Anderson KC
影响因子：
11.4
作者：
Paiva, B.;Perez-Andres, M.;Orfao, A.
通讯作者：
Orfao, A.