Trib1 promotes the development of acute myeloid leukemia in a Ts1Cje mouse model of Down syndrome
Trib1 promotes the development of acute myeloid leukemia in a Ts1Cje mouse model of Down syndrome
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Trib1 促进唐氏综合症 Ts1Cje 小鼠模型中急性髓系白血病的发展
DOI：
10.1038/s41375-021-01384-1
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发表时间：
2021
期刊：
影响因子：
11.4
通讯作者：
Nakamura Takuro
中科院分区：
文献类型：
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作者：
Yoshino Seiko;Tanaka Miwa;Sunami Yoshitaka;Takahara Tomoko;Yamazaki Yukari;Homme Mizuki;Niibori-Nambu Akiko;Osato Motomi;Minami Takashi;Ishihara Keiichi;Nakamura Takuro
唐氏综合征（DS）是由21号染色体三体引起的，是世界上最常见的遗传性疾病，每700个活产婴儿中就有1个受到影响。DS患者表现出各种临床表现，包括智力残疾、心血管畸形、面部畸形、免疫缺陷和易患造血系统肿瘤。大约10%的DS儿童表现出短暂性骨髓增生性疾病（TMD）的临床表现，其特征是未成熟巨核母细胞显著增加[1]。正常情况下，TMD会在一个月内自发消退;然而，30%的TMD患者随后会发展为急性巨核细胞白血病（DS-AMKL）[1，2]。此外，患有DS的个体显示出发生急性B淋巴细胞白血病的倾向，这表明21三体是白血病发生的重要风险因素[2]。几乎所有病例中，TMD的发生均与获得性GATA 1突变相关[3，4]。对DSAMKL的综合基因组分析已经确定了几种基因中的复发性体细胞突变，包括CCCTC结合因子、zeste增强子2多梳抑制复合物2亚基、神经母细胞瘤RAS病毒癌基因同源物、基质抗原2和RAD 21粘附素复合物组分[5]，表明GATA 1突变可能不是DS-AMKL发生的唯一原因。我们之前已经在DS-AMKL病例中鉴定了tribbles假激酶1（TRIB 1）中的功能获得性突变，TRIB 1是一种充当分子衔接子的假激酶蛋白[6]。TRIB 1招募E3泛素连接酶组成型光形态发生1蛋白（COP 1）降解髓系肿瘤抑制因子C/EBPα，同时与MEK 1相互作用维持细胞外信号调节蛋白激酶1/2（ERK 1/2）的磷酸化[7]。检测到的TRIB 1 R107 L突变促进C/EBPα的降解和MEK/ERK信号传导的增强，尽管该突变在DS-AMKL中罕见，并且尚未在其他TMD和DS-AMKL患者中发现[7，8]。这些结果表明，结合三体21，TRIB 1介导的信号转导可能参与DS相关髓系白血病的发展。已经产生了多个DS小鼠模型，其具有三个人类21号染色体拷贝[9]。人类21号染色体的大部分位于小鼠16号染色体的端粒区。Ts 1Cje小鼠系为16号染色体的一个片段的三体，该片段与人21号染色体的约70个基因的区域同线，包括负责DS表型的主要基因[10]。先前的研究表明，Ts 1Cje小鼠的造血干细胞和祖细胞功能受损;然而，这些小鼠不会发生血小板增多症或急性髓细胞白血病（AML）[11]。此外，Ts 1Cje和Gata 1突变小鼠杂交的后代不会发生白血病[11]。在这项研究中，我们的目的是将Trib 1引入Ts 1Cje小鼠，以检查Trib 1表达与21三体相结合是否促进白血病的发展。通过5-氟尿嘧啶（5-FU）处理富集Ts 1Cje或C57 B16/J小鼠的造血干/祖细胞，并用野生型或R107 L突变体Trib 1 cDNA进行逆转录病毒转导。如先前关于LSK细胞的报道[10]，TslCje小鼠中5-FU处理的骨髓细胞的数量显著减少（图1A）。用Trib 1野生型或R107 L突变体携带逆转录病毒转导骨髓细胞，并将其移植到致死辐射（8.5戈伊）的B6小鼠中。野生型和R107 L Trib 1在Ts 1Cje骨中的表达
Down syndrome (DS), caused by the trisomy of chromosome 21, is the most common genetic disorder worldwide, affecting~ 1 in 700 live births. Individuals with DS exhibit various clinical manifestations, including intellectual disability, cardiovascular malformations, facial dysmorphia, immunodeficiency, and predisposition to hematopoietic neoplasms. Approximately 10% of children with DS show clinical manifestation of transient myeloproliferative disorder (TMD), characterized by a significant increase in immature megakaryoblasts [1]. Normally, TMD spontaneously regresses within a month; however, 30% of patients with TMD subsequently develop acute megakaryocytic leukemia (DS-AMKL) afterwards [1, 2]. Moreover, individuals with DS show a predisposition to develop acute B-lymphoblastic leukemia, suggesting that trisomy 21 is an important risk factor for leukemia development [2]. The development of TMD is associated with acquired GATA1 mutations in almost all cases [3, 4]. Comprehensive genomic analysis of DSAMKL has identified recurrent somatic mutations in several genes including CCCTC-binding factor, enhancer of zeste 2 polycomb repressive complex 2 subunit, neuroblastoma RAS viral oncogene homolog, stromal antigen 2, and RAD21 cohesin complex component [5], indicating that the GATA1 mutations may not be the only cause of DS-AMKL development. We have previously identified a gain-of-function mutation in tribbles pseudokinase 1 (TRIB1), a pseudokinase protein that acts as a molecular adaptor, in a case of DS-AMKL [6]. TRIB1 recruits an E3 ubiquitin ligase constitutive photomorphogenesis 1 protein (COP1) to degrade the myeloid tumor suppressor C/EBPα, and at a same time, it interacts with MEK1 to sustain phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2)[7]. The detected TRIB1 R107L mutation promotes both the degradation of C/EBPα and the enhancement of MEK/ERK signaling, although this mutation is rare in DS-AMKL and has not been identified in the other TMD and DS-AMKL patients [7, 8]. These results suggest that combined with trisomy 21, TRIB1-mediated signaling may be involved in the development of DS-associated myeloid leukemia. Multiple mouse models of DS, which possess three copies of human chromosome 21, have been generated [9]. Most parts of human chromosome 21 are located in the telomeric region of the mouse chromosome 16. The Ts1Cje mouse line is trisomic for a segment of chromosome 16 that is syntenic to the region containing~ 70 genes of the human chromosome 21, including major genes responsible for the DS phenotype [10]. A previous study demonstrated that the functions of hematopoietic stem and progenitor cells are impaired in Ts1Cje mice; however, these mice do not develop thrombocytosis or acute myeloid leukemia (AML)[11]. Furthermore, the progeny of a cross between Ts1Cje and Gata1 mutant mice does not develop leukemia [11]. In this study, we aimed to introduce Trib1 into Ts1Cje mice to examine whether Trib1 expression combined with trisomy 21 facilitated the development of leukemia. Hematopoietic stem/progenitor cells of Ts1Cje or C57Bl6/J mice were enriched by 5-fluorouracil (5-FU) treatment and retrovirally transduced with wild-type or R107L mutant Trib1 cDNAs. As previously reported for LSK cells [10], the number of 5-FU-treated bone marrow cells was significantly reduced in Ts1Cje mice (Fig. 1 A). Bone marrow cells were transduced with Trib1 wild-type or R107L mutantbearing retrovirus and they were transplanted into lethally irradiated (8.5 Gy) B6 mice. Expression of both wild-type and R107L Trib1 in Ts1Cje bone …