Role of MN1-TEL and MN1 in Leukemogenesis

描述(申请人提供)：反复的染色体易位t(12；22)(p12；q11)与骨髓增殖性疾病和急性髓系白血病(AML)有关，并创造了MN1-TEL融合基因，其中编码转录因子TEL的N-末端区域的序列被几乎整个转录共激活因子MN1的编码序列所取代。我们已经证明MN1-TEL是一种癌基因，可以刺激造血细胞的生长并增加其自我更新的潜力。MN1-TEL本身不足以引起造血系统疾病，但它与同源框蛋白HOXA9的过度表达一起在小鼠中引起AML，这种组合也在t(12；22)患者样本中发现。令人惊讶的是，MN1单独在小鼠骨髓中的过度表达迅速诱导了骨髓增生性疾病(MPD)。此外，编码CBFP-MYH11融合蛋白的16号倒位染色体(Inv16)的AML患者的MN1基因表达也上调，在过度表达永生化基因EVIS的AML患者中，CBFP-MYH11和MN1在小鼠骨髓中的共表达导致AML的快速发展，强烈提示两种蛋白之间存在功能上的协同作用。这表明MN1在髓系恶性肿瘤中的作用比以前所知的更广泛，并且远远超出了它在t(12；22)中的参与。尽管我们确定MN1可以与转录共激活因子p300和RAC相互作用，并刺激HeLa细胞中维甲酸受体的转录，但我们对涉及MN1和MN1-TEL的机制知之甚少。因此，将对转化的小鼠髓系细胞中的MN1和MN1-TEL转录复合体进行广泛的分析，并确定这些转录因子的直接转录靶基因(特定目标1)。我们将利用Mn1基因敲除小鼠来确定Mn1在正常骨髓生成中的作用。通过使用逆转录病毒突变和引入定向突变，我们将确定哪些基因损伤在白血病发生中与MN1-TEL和MN1合作。总之，这些研究应该为MN1-TEL和MN1白血病涉及的分子机制和遗传途径提供广泛的见解。这些研究也应该为开发涉及这些转录因子的AML的新疗法提供线索。

DESCRIPTION (provided by applicant): The recurrent chromosome translocation t(12;22)(p12;q11) is associated with myeloproliferative disorders and acute myeloid leukemia (AML), and creates an MN1-TEL fusion gene in which the sequence encoding the N-terminal region of the transcription factor TEL is replaced by almost the entire coding sequence of the transcriptional coactivator MN1. We have shown that MN1-TEL is an oncogene that stimulates growth of hematopoietic cells and increases their self-renewal potential. MN1-TEL alone is insufficient to cause hematopoietic disease, but it causes AML in mice in cooperation with overexpression of the homeobox protein HOXA9, a combination also found in t(12;22) patient samples. Surprisingly, overexpression of MN1 alone in bone marrow of mice rapidly induced myeloproliferative disease (MPD). In addition, MN1 gene expression is also upregulated in samples of AML patients characterized by inversion chromosome 16 (inv16), which encodes the CBFP-MYH11 fusion protein, and in AML samples overexpressing the immortalizing gene EVIL Moreover, coexpression of CBFP-MYH11 and MN1 in mouse BM led to rapid development of AML, strongly suggesting a functional cooperation between two proteins. This suggests that the role of MN1 in myeloid malignancy in more extensive than previously known and goes well beyond its involvement in the t(12;22). Although we determined that MN1 can interact with the transcription coactivators p300 and RAC and stimulates transcription of the retinoic acid receptor in HeLa cells, we know little about the mechanistic pathways that involve MN1 and MN1-TEL in myeloid cells. Therefore, extensive analysis will be performed of MN1 and MN1-TEL transcription complexes in transformed mouse myeloid cells and direct transcriptional target genes of these transcription factors will be identified (Specific Aim 1). Mn1 knockout mice we will be used to determine the role of Mn1 in normal myelopoiesis. By using retroviral mutagenesis and introduction of directed mutations we will determine which genetic lesions cooperate with MN1-TEL and MN1 in leukemogenesis. Together these studies should provide extensive insights into the molecular mechanism and genetic pathways involved in MN1-TEL and MN1 leukemia. These studies should also provide leads for the development of novel therapies for AML involving these transcription factors.