MLL AF4 LEUKEMIA

描述：（由申请人提供）本提案的总体目标是 了解MLL-AF 4，也称为t（4;l1），白血病。这是最常见的 婴儿白血病，预后差;也见于年龄较大的儿童 和成年人。我们最近开发了“基因敲入”技术， 胚胎干（ES）MLL-AF 4细胞。我们证明MLL-AF 4融合蛋白 在胚胎干细胞中抗凋亡，并在更多的造血干细胞中阻断造血分化。 成熟细胞我们预测MLL-AF 4 ES细胞衍生的白血病小鼠 将具有在人MLL-AF 4白血病中所见的相同的特异性表型。我们将 评估人类MLL-AF 4白血病预后不良的假设， 结果从抵抗细胞凋亡;在人类，细胞凋亡发生在良好的 生长因子剥夺或化疗后白血病的预后 MLL-AF 4白血病我们有三个修订的具体目标：（1）评估 假设融合基因是抗凋亡，而AF 4融合基因是 对于这种效果至关重要。分化将使用胚状体进行研究 和造血集落培养系统。条件MLL-AF 4表达 系统将被开发来控制基因表达，并允许生存的 活的祖细胞(2)为了评估假设， MLL-AF 4融合基因具有细胞类型特异性。(3)为了研究具有MLL-AF 4或 MLL-AF 9融合基因白血病。

DESCRIPTION: (provided by applicant) The overall objective of this proposal is to understand MLL-AF4, also known as t(4;l1), leukemia. This is the most common leukemia in infants and has a poor prognosis; it is also seen in older children and adults. We have recently developed "knock-in" technology to produce murine embryonic stem (ES) MLL-AF4 cells. We demonstrated that MLL-AF4 fusion protein is anti-apoptotic in ES cells and blocks hematopoietic differentiation in more mature cells. We predict that mice with leukemia derived from MLL-AF4 ES cells will have the same specific phenotype seen in human MLL-AF4 leukemia. We will evaluate the hypothesis that the poor prognosis of human MLL-AF4 leukemia results from resistance to apoptosis; in humans, apoptosis occurs in good prognosis leukemias following growth factor deprivation or chemotherapy but not in MLL-AF4 leukemia. We have three revised specific aims: (1) To evaluate the hypothesis that fusion gene is anti-apoptotic and the AF4 fusion gene is critical for this effect. Differentiation will be studied using embryoid body and hematopoietic colony culture systems. Conditional MLL-AF4 expression systems will be developed to control gene expression and permit survival of viable progenitor cells. (2) To evaluate the hypothesis that the effects of MLL-AF4 fusion gene are cell-type specific. (3) To study mice with MLL-AF4 or MLL-AF9 fusion gene leukemia.