Cancer cell：急性髓细胞性白血病相关的新蛋白Tribbles被发现
生物谷报道：
这种蛋白质名为Tribbles，它与人类恶性肿瘤的直接关系是第一次被阐述。这是一种新的人类癌症相关蛋白，在造血干细胞中表达时具有极其重要及特殊的意义。AML是成人最常见的白血病类型，每年约有10100例新发病例。
Figure 2. Trib2 induces AML
A: Kaplan-Meier survival curve of mice receiving Trib2-transduced BM compared to MigR1 control. The median survival of Trib2 mice was 179 days. Results are derived from seven independent experiments.
B: Representative photographs of splenomegaly in Trib2 mice compared to control MigR1 spleen, and lymphadenopathy in Trib2 mice.
C: Wright-Giemsa-stained PB and BM single cell suspensions from MigR1 and leukemic Trib2 mice. Scale bars (upper right) represent 10 μm. The percentage of GFP+ cells in Trib2 BM was approximately 90%–100%.
D: Histopathology of BM sections from Trib2-induced AML. Hematoxylin and eosin (H+E) section showing hypercellularity (top left) due to the presence of sheets of immature cells and blasts (top right). The tumor cells stain positively for myeloperoxidase (MPO, bottom left) and negatively for terminal deoxytransferase (TdT, bottom right). Scale bars (lower right) represent 20 μm.
Tribbles是Pear及其同事们在研究另一个蛋白质Notch时偶然发现的。有一些证据支持Tribbles与AML有关。第一，对小鼠进行基因修饰，使其造血干细胞中表达Tribbles-2(Trib-2)后，这些小鼠均发生AML。第二，AML时C/EBPa常发生突变，而Trib-2抑制了此蛋白的作用。第三，AML患者血样中Tribbles蛋白水平升高。综上所述，这些结果显示，Tribbles通过抑制C/EBPa蛋白诱发AML。果蝇中的实验证明Tribbles蛋白与细胞生长及决定细胞命运有关， Tribbles如果发生突变，将会导致细胞无限制增殖。
越来越多的证据表明，Tribbles实际上起到一个支架的作用，将多种物质结合在一起形成复合体，调节蛋白降解。正常细胞功能需要蛋白降解，但Tribbles基因的表达错误将导致抑制肿瘤的蛋白如肿瘤抑制因子降解。研究人员现在的任务就是，明确Tribbles还可能引起哪些蛋白降解从而导致肿瘤。
对AML患者基因表达的筛查中发现，C/EBPa缺陷的患者Tribbles基因表达水平升高。肺癌及其他肿瘤时也发生C/EBPa缺陷，提示在其他肿瘤中也存在Trib2失调。
Trib2与人类肿瘤有关，这更进一步支持通过作用于蛋白质降解过程来治疗恶性肿瘤的思路。
研究资金由美国国立卫生研究所、白血病与淋巴瘤学会、Damon Runyon癌症研究基金提供。
原文出处：
Cancer cell November, 2006: 10 (5) 401－412
Tribbles homolog 2 inactivates C/EBPα and causes acute myelogenous leukemia
Karen Keeshan, Yiping He, Bas J. Wouters, Olga Shestova, Lanwei Xu, Hong Sai, Carlos G. Rodriguez, Ivan Maillard, John W. Tobias, Peter Valk, Martin Carroll, Jon C. Aster, Ruud Delwel, and Warren S. Pear
全文下载：[Summary] [Full Text] [PDF] [Supplemental Data]
相关知识：
Pubmed OMIM：急性髓细胞白血病（AML）
LEUKEMIA, ACUTE MYELOID; AML
Alternative titles; symbols
LEUKEMIA, ACUTE MYELOGENOUS
A number sign (#) is used with this entry because acute myeloid leukemia (AML) can be caused by somatic mutation in the ETV6 gene (600618) and the JAK2 gene (147796). Other causes of AML include fusion genes generated by chromosomal translocations; see, for example, 600358 and 159555.
Baozhang et al. (1999) reported a family with 7 cases of related leukemias among 22 members in 3 consecutive generations consistent with autosomal dominant inheritance. One of the patients and her father were found to have rearrangement and a rearrangement/amplification, respectively, of the ERBB oncogene (131550).
Horwitz et al. (1996) reported evidence of anticipation in familial acute myelogenous leukemia. Horwitz et al. (1996) further studied those pedigrees and others from the literature. In 49 affected individuals from 9 families transmitting autosomal dominant AML, the mean age of onset was 57 years in the grandparental generation, 32 years in the parental generation, and 13 years in the youngest generation (P less than 0.001). Horwitz et al. (1996) also reported evidence of anticipation in autosomal dominant chronic lymphocytic leukemia (CLL; 151400) (P = 0.008). In 18 affected individuals from 7 pedigrees with autosomal dominant CLL, the mean age of onset in the parental generation was 66 years, versus 51 years in the younger generation. Based on this evidence of anticipation, Horwitz et al. (1996) suggested that dynamic mutations of unstable DNA sequence repeats could be a common mechanism of inherited hematopoietic malignancy. They proposed 3 possible candidate chromosomal regions for familial leukemia with anticipation: 21q22.1-22.2, 11q
See 601399 for a description of familial platelet disorder, which predisposes to acute myeloid leukemia. This disorder behaves as an autosomal dominant trait; it is caused by mutation in the CBFA2 gene (151385).
Bone marrow minimal residual disease causes relapse after chemotherapy in patients with acute myelogenous leukemia. Matsunaga et al. (2003) postulated that the drug resistance is induced by the attachment of very late antigen-4 (VLA4; see 192975) on leukemic cells to fibronectin (135600) on bone marrow stromal cells. Matsunaga et al. (2003) found that VLA4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (see 601232)/AKT (164730)/Bcl2 (151430) signaling pathway, which is activated by the interaction of VLA4 and fibronectin. This resistance was negated by VLA4-specific antibodies. In a mouse model of minimal residual disease, Matsunaga et al. (2003) achieved a 100% survival rate by combining VLA4-specific antibodies and cytosine arabinoside, whereas cytosine arabinoside alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA4-negative patients and 44.4% for 15 VLA4-positive patients. Thus, Matsunaga et al. (2003) concluded that the interaction between VLA4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow minimal residual disease and AML prognosis.
Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2005) analyzed 300 patients newly diagnosed with AML for mutations in the coding region of the ETV6 gene and identified 5 somatic heterozygous mutations (e.g., 600618.0001 and 600618.0002). These ETV6 mutant proteins were unable to repress transcription and showed dominant-negative effects. The authors also examined ETV6 protein expression in 77 patients with AML and found that 24 (31%) lacked the wildtype 57- and 50-kD proteins; there was no correlation between ETV6 mRNA transcript levels and the loss of ETV6 protein, suggesting posttranscriptional regulation of ETV6.
Lee et al. (2006) identified heterozygosity for mutations in the JAK2 gene (147796.0001 and 147796.0002) in bone marrow aspirates from 3 (2.7%) of 113 unrelated patients with AML.
1. Baozhang, F.; Jianling, L.; Zexi, L.; Jianping, H.; Wenjie, C. :
Genetic studies on a family with acute myelogenous leukemia. Cancer Genet. Cytogenet. 112: 134-137, 1999.
PubMed ID : 10686940
2. Barjesteh van Waalwijk van Doorn-Khosrovani, S.; Spensberger, D.; de Knegt, Y.; Tang, M.; Lowenberg, B.; Delwel, R. :
Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia. Oncogene 24: 4129-4137, 2005.
PubMed ID : 15806161
3. Horwitz, M.; Goode, E. L.; Jarvik, G. P. :
Anticipation in familial leukemia. Am. J. Hum. Genet. 59: 990-998, 1996.
PubMed ID : 8900225
4. Horwitz, M.; Sabath, D. E.; Smithson, W. A.; Raddich, J. :
A family inheriting different subtypes of acute myelogenous leukemia. Am. J. Hemat. 52: 295-304, 1996.
PubMed ID : 8701948
5. Lee, J. W.; Kim, Y. G.; Soung, Y. H.; Han, K. J.; Kim, S. Y.; Rhim, H. S.; Min, W. S.; Nam, S. W.; Park, W. S.; Lee, J. Y.; Yoo, N. J.; Lee, S. H. :
The JAK2 V
PubMed ID : 16247455
6. Matsunaga, T.; Takemoto, N.; Sato, T.; Takimoto, R.; Tanaka, I.; Fujimi, A.; Akiyama, T.; Kuroda, H.; Kawano, Y.; Kobune, M.; Kato, J.; Hirayama, Y.; Sakamaki, S.; Kohda, K.; Miyake, K.; Niitsu, Y. :
Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nature Med. 9: 1158-1165, 2003. Note: Erratum: Nature Med. 11: 578 only, 2005.
PubMed ID : 12897778
Cassandra L. Kniffin - updated :
Marla J. F. O'Neill - updated : 4/12/2006
Ada Hamosh - updated : 8/26/2003
Victor A. McKusick - updated : 11/17/1999
Moyra Smith :
wwang :
ckniffin : 6/20/2006
wwang : 4/12/2006
terry : 4/12/2006
mgross : 5/17/2005
tkritzer : 2/7/2005
alopez : 9/2/2003
alopez : 8/26/2003
terry : 8/26/2003
carol : 11/13/2001
mgross : 12/6/1999
terry : 11/17/1999
mark : 1/14/1997
mark : 1/14/1997
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