MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.
MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.
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MYBL2 是骨髓恶性肿瘤中的亚单倍体不足抑癌基因。
DOI：
10.7554/elife.00825
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发表时间：
2013-07-16
期刊：
影响因子：
7.7
通讯作者：
Look AT
中科院分区：
文献类型：
--
作者：
Heinrichs S;Conover LF;Bueso-Ramos CE;Kilpivaara O;Stevenson K;Neuberg D;Loh ML;Wu WS;Rodig SJ;Garcia-Manero G;Kantarjian HM;Look AT
骨髓增生异常综合征（MDS）和骨髓增生性肿瘤（MPN）中的共同缺失区（CDR）影响20号染色体的长臂，并已被预测含有肿瘤抑制基因。在这里，我们表明，MYBL 2，20 q CDR内的基因，表达在急剧下降的水平在CD 34+细胞从大多数MDS病例（65%; n = 26），无论他们是否窝藏20 q异常。在鼠竞争性重建模型中，通过RNAi将Mybl 2敲低至多能造血祖细胞中正常水平的20-30%导致这些“亚单倍体不足”细胞的克隆优势，这反映在所有血细胞谱系中。到移植后6个月，重建的小鼠已经发展出源自Mybl 2表达异常降低的细胞的克隆性骨髓增生性/骨髓增生异常疾病。我们的结论是，下调MYBL 2活性低于经典的单倍不足预测的水平的基础造血祖细胞在很大一部分的人骨髓恶性肿瘤的克隆扩增。http://dx.doi.org/10.7554/eLife.00825.001血细胞是由骨髓中的特化干细胞和祖细胞产生的。这一过程的异常会导致一组被称为骨髓恶性肿瘤的疾病，包括急性骨髓性白血病（骨髓产生异常的白色血细胞）和骨髓增生异常综合征（产生的成熟血细胞过少）。受这些疾病影响的许多个体具有缺少许多基因的20号染色体的缩短形式。这种缺失只出现在两个染色体拷贝中的一个，这表明这些基因中至少有一些是生存所必需的，但是与骨髓恶性肿瘤风险增加相关的基因的身份尚不清楚。现在，海因里希斯等人在20号染色体上经常丢失的基因中发现了一个关键的肿瘤抑制基因。这种基因被称为MYBL 2，编码一种有助于控制细胞分裂周期的转录因子。缺乏该基因的一个拷贝的骨髓恶性肿瘤患者显示MYBL 2表达水平低于健康个体的50%。这表明，其他机制必须发挥作用，以减少其剩余的基因拷贝的表达。令人惊讶的是，MYBL 2水平在具有20号染色体的两个完整拷贝的骨髓恶性肿瘤患者中也降低，表明单个拷贝的丢失仅代表降低MYBL 2表达的一种机制，即，"冰山一角“因此，这一发现揭示了MYBL 2更普遍的作用，因为它表明更多的患者可能受到该基因表达改变的影响。为了证实他们在患者研究中的发现，海因里希斯等人使用基因沉默技术来减少小鼠中MYBL 2的表达，并表明这在动物中诱导了骨髓恶性肿瘤的症状。此外，将这些动物的修饰细胞注射到健康小鼠中也会引起受体的症状。修饰的细胞能够比正常细胞更稳健地扩增，并且这种由肿瘤抑制因子下调诱导的优势增加了恶性肿瘤的风险。除了揭示一种新的肿瘤抑制基因及其对骨髓恶性肿瘤的作用外，海因里希斯等人的研究还强调了基因剂量在介导肿瘤抑制因子作用中的重要性。DOI：http://dx.doi.org/10.7554/eLife.00825.002网站
A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20–30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these ‘sub-haploinsufficient’ cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies. DOI: http://dx.doi.org/10.7554/eLife.00825.001 Blood cells are produced within bone marrow by specialized stem cells and progenitor cells. Abnormalities in this process lead to a group of diseases known as myeloid malignancies, which include acute myeloid leukaemia—in which the bone marrow produces abnormal white blood cells—and myelodysplastic syndromes, which are caused by too few mature blood cells being produced. Many individuals affected by these disorders possess a shortened form of chromosome 20 that lacks a number of genes. This deletion is only ever seen in one of their two copies of the chromosome—suggesting that at least some of these genes are essential for survival—but the identity of the gene(s) that are associated with the increased risk of myeloid malignancies is unknown. Now, Heinrichs et al. have uncovered a key tumor suppressor among those genes frequently lost on chromosome 20. The gene, which is called MYBL2, encodes a transcription factor that helps to control the cell division cycle. Myeloid malignancy patients lacking one copy of this gene showed levels of MYBL2 expression that were less than 50% of those in healthy individuals. This suggests that additional mechanisms must be acting to reduce expression of their remaining copy of the gene. Surprisingly, MYBL2 levels were also reduced in myeloid malignancy patients who possessed two intact copies of chromosome 20, indicating that loss of a single copy represents only one mechanism to reduce MYBL2 expression, i.e., the ‘tip-of-the-iceberg’. Hence, this finding reveals a more general role for MYBL2 as it indicates that more patients are likely to be affected by altered expression of this gene. To confirm their findings from studies in patients, Heinrichs et al. used gene silencing techniques to reduce the expression of MYBL2 in mice and showed that this induced symptoms of myeloid malignancies in the animals. Moreover, injection of modified cells from these animals into healthy mice also induced symptoms in the recipients. The modified cells are able to expand more robustly than normal cells, and this dominance induced by downregulation of the tumor suppressor increases the risk of malignancy. In addition to revealing a new tumor suppressor gene and its contribution to myeloid malignancies, the study by Heinrichs et al. highlights the importance of gene dosage in mediating the effects of tumor suppressors. DOI: http://dx.doi.org/10.7554/eLife.00825.002