11月16日，美国宾西法尼亚大学医学院研究人员发现了与急性髓细胞白血病（AML）有关的新型蛋白质。研究发表于本周《肿瘤细胞》杂志。
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
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相关知识：
Pubmed OMIM：急性髓细胞白血病（AML）
#601626
LEUKEMIA, ACUTE MYELOID; AML
Alternative titles; symbols
LEUKEMIA, ACUTE MYELOGENOUS
Gene map locus 21q22.3, 19q13.1, 19p13.3, 16q22, 13q12, 12p13, 11q23.3, 11q14, 10p12, 9q34.1, 9p24, 8p12, 5q35, 5q35, 4q12, 4q11-q12, 3q28, 3q25.1, 3q24
TEXT
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, 11q23.3 in the vicinity of the CBL2 gene (165360), and 16q22 in the vicinity of the CBFB gene (121360).
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.
REFERENCES
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 V617F mutation in de novo acute myelogenous leukemias. Oncogene 25: 1434-1436, 2006.
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
CONTRIBUTORS
Cassandra L. Kniffin - updated : 6/20/2006
Marla J. F. O'Neill - updated : 4/12/2006
Ada Hamosh - updated : 8/26/2003
Victor A. McKusick - updated : 11/17/1999
CREATION DATE
Moyra Smith : 1/14/1997
EDIT HISTORY
wwang : 6/23/2006
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
mark : 1/14/1997
作者简介：
Warren S. Pear, M.D., Ph.D.
Associate Professor, Dept of Pathology and Laboratory Medicine
Abramson Family Cancer Research Institute
Institute for Medicine and Engineering
Research Interests
Tumor Biology, Development, Stem Cells, Hematopoiesis
Research Techniques: In vivo and in vitro models of hematopoiesis and transformation, retroviral transduction, bone marrow transplantation, ES cell culture and differentiation, cDNA cloning, cell sorting, video microscopy, knockout and RNAi technology
Search PubMed for articles
Description of Research
A major area of interest of this laboratory is understanding the processes that lead to the development and differentiation of mature hematopoietic cells from a single hematopoietic stem cell. We are particularly interested in studying the processes that perturb these normal processes and cause leukemia. A primary focus of the laboratory is the role that Notch proteins play in regulating hematopoietic cell fate decisions and cancer. Notch proteins are a conserved family of receptors that regulate cell fate decisions in organisms ranging from Drosophila to humans. Using a variety of in vitro and in vivo approaches, we have shown that Notch proteins are key regulators of multiple hematopoietic cell fates. These include establishment of the T cell lineage and helper type 2 T cells. We are presently undertaking studies to identify the signaling pathways that control these and other cell fate decisions in hematopoiesis. In addition to their role in normal hematopoiesis, dysregulation of Notch signaling is a cause of human leukemia. We have developed a mouse model of Notch-related leukemia and are using this to study the signaling pathways that lead to oncogenic transformation. Using gene array and bioinformatics approaches, we have identified several direct transcriptional targets of Notch signaling that appear to mediate its effects in normal development and leukemia. In addition, we are developing and testing ways to block Notch signaling that may be useful in treating leukemia and other Notch-dependent diseases.
Recent Publications
Maillard, I., Weng, A.P., Carpenter, A.C., Rodriguez, C.G., Sai, H., Xu, L., Allman, D., Aster, J.C., and Pear, W.S., Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood 104, 1696-702, 2004.
Tu, L., Fang, T.C., Artis, D., Shestova, O., Pross, S., Maillard, I., Pear, W.S., Notch signaling is a critical regulator of type 2 immunity. J. Exp. Med., 8, 1037-1042: 2005.
McKay, P.Z., He, Y., Xu, L., Rodriguez, C.G., Karnell, F.G., Carpenter, A.C., Aster, J.C., Allman, D., and Pear, W.S., Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B cell malignancies. Blood 106, 3898-3906, 2005.
Weng, A.P., Millholland, J.M., Yashiro-Ohtani, Y., Arcangeli, M.L., Lau, A., Wai, C., del Bianco, C., Rodriguez, C.G., Sai, H., Tobias, J., Li, Y., Wolfe, M.S., Shachaf, C., Felsher, D., Blacklow, S.C., *Pear, W.S., *Aster, J.C., c-Myc is an important direct target of Notch1 in T cell acute lymphoblastic leukemia/lymphoma. Genes Dev., 20, 2096-2109, 2006. *Corresponding Authors
Keeshan, K., He, Y., Wouters, B.J., Shestova, O., Xu, L., Sai, H., Rodriguez, C., Maillard, I., Tobias, J.W., Valk, P., Carroll, M., Aster, J.C. Delwel, R., and Pear, W.S., Tribbles homologue 2 (Trib2) inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell, 2006, in the press.
Lab
Rotation Projects for 2006-2007
1. Characterization of Notch transcriptional targets in hematopoiesis and leukemia. This project will characterize potential direct transcriptional targets of Notch signaling that we have identified in a microarray screen. The project will involve verifying that these are direct transcriptional targets using chromatin immunoprecipitation (ChIP), EMSA, and reporter assays and then testing whether these targets are functionally important using retroviral transduction, apoptosis, proliferation, and differentiation in both primary and established cell lines.
2. Identification of genes that potentiate Notch transforming activity. We have induced a number of Notch T cell leukemias using retroviruses that express activated forms of Notch1. The retroviral vectors also contain enhancer elements that can activate transcription of genes in the vicinity of their integration site. We have established techniques to rapidly clone the genes that are activated by retroviral vector integration and will use both in vitro and in vivo assays to determine if they synergize with Notch to induce leukemia.
3. We have identified Tribbles as a novel oncogene in acute myelogenous leukemia. Very little is know about Tribbles function. This project will use biochemical and functional assays to determine the function of Tribbles in leukemia and normal hematopoietic development.
Lab personnel:
Mark Chiang, Postdoctoral Fellow
Priya Dedhia, Graduate Student
Terry Fang, Graduate Student
Karen Keeshan, Postdoctoral Fellow
Ivan Maillard, Postdoctoral Fellow
Takuya Ohtani, Postdoctoral Fellow
Yumi Ohtani Postdoctoral Fellow
Hong Sai Research Specialist
Andras Schaffer, Postdoctoral Fellow
Olga Shestova Research Specialist
Maria Vega, PREP student
Lanwei Xu Research Specialist
