Oncogenes in murine acute myeloid leukemia

在小鼠骨髓性白血病发生模型中，c-myb基因是插入的主要目标。该实验室最近的一个重点是阐明c-Myb在白血病进展中的生物学作用，并确定在转录水平上受c-Myb调节的特定基因。我们发现c-Myb通过多种机制转化细胞，包括：1)通过直接反激活细胞增殖基因（如c-myc）和防止肿瘤抑制因子单核细胞的上调来积极调节细胞生长；2)通过反激活Bcl-2来抑制细胞凋亡。c-Myb影响肿瘤抑制因子表达的方式是我们最近对Myb转化研究的主题。有趣的是，我们发现，在c-Myb转化细胞和分化表达c-Myb的骨髓细胞中，肿瘤抑制因子p15Ink4b（一种cdk抑制剂）被特异性地阻止开启。这是组成表达c-Myb的细胞的特征，而不是那些组成表达B-Myb或c-Myc的细胞的特征。在正常细胞中，这种肿瘤抑制因子在分化过程中被上调，并与髓细胞的生长停滞有关。我们证实，在我们的c-myb通过插入突变激活的白血病中，p15Ink4b基因没有甲基化，因为它在绝大多数人类aml和人类和小鼠起源的淋巴瘤中都是如此。我们最近的研究表明，c-Myb作为一种转录因子具有多种作用，可以单独促进白血病细胞的生长。

In a murine model for myeloid leukemogenesis, the c-myb gene is a primary target of insertional. A recent focus of the laboratory has been to clarify the biological roles of c-Myb in leukemia progression and identify specific genes that are regulated by c-Myb at the transcriptional level. We have found that c-Myb transforms cells through multiple mechanisms including: 1) positive regulation of cell growth by both directly transactivating a cell proliferation gene(s) such as c-myc as well as preventing upregulation in monocytic cells of tumor suppressor(s) 2) inhibition of apoptosis by transactivating Bcl-2. The way in which c-Myb affects tumor suppressor expression is the subject of our most recent research on Myb transformation. Interesting, we have found that, in c-Myb transformed cells and in differentiating myeloid cells constitutively expressing c-Myb, the tumor suppressor p15Ink4b, a cdk inhibitor, is specifically prevented from being turned on. This is a characteristic of cells constitutively expressing c-Myb, but not those constitutively expressing B-Myb or c-Myc. In normal cells this tumor suppressor is upregulated during differentiation and associated with growth arrest of myeloid cells. We confirmed that in our leukemias in which the c-myb is activated by insertional mutagenesis the p15Ink4b gene is not methylated as it is in a great majority of human AMLs and lymphomas of human and murine origin. Our recent studies contribute to the idea that c-Myb has several roles as a transcription factor that individually can enhance leukemia cell outgrowth.