Role of MN1-TEL and MN1 in Leukemogenesis

点击翻译按钮获取中文摘要

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.