Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Disease, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Center for Precision Medicine, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Disease, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Leukemia. 2019 Feb;33(2):469-486. doi: 10.1038/s41375-018-0222-x. Epub 2018 Aug 8.
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.
尽管在多发性骨髓瘤（MM）的治疗方面取得了进展，包括使用大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均产生耐药性。这种耐药性与 MM 细胞中的分子遗传异质性以及骨髓（BM）的贡献有关，而 BM 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 异质性与静止的干细胞样癌细胞的存在有关，这些细胞更喜欢存在于 BM 的成骨细胞龛中。在本报告中，我们鉴定了一种新型蛋白，即三结构域蛋白 44（TRIM44），其在 BM 的成骨细胞龛中过度表达，使 MM 细胞能够与 HSCs 竞争龛位支持。MM 细胞中的 TRIM44 表达促进细胞静止，但增加了异种移植小鼠的骨破坏，与 MM 患者的观察结果相似。TRIM44 作为缺氧诱导因子-1α（HIF-1α）的去泛素化酶发挥作用，在缺氧和常氧条件下稳定 HIF-1α的表达。稳定的 HIF-1α 刺激 MM 细胞在缺氧时的生长和存活。我们的工作首次揭示了静止 MM 细胞中的信号转导和 TRIM44 的功能。
