MLL AF4 LEUKEMIA

描述：(申请人提供)本提案的总体目标是 了解MLL-AF4，又称t(4；L1)，白血病。这是最常见的 婴儿中的白血病，预后很差；它也见于较大的儿童 和成年人。我们最近开发了“敲入”技术来生产老鼠 胚胎干细胞MLL-AF4细胞。我们证明了MLL-AF4融合蛋白 在ES细胞中具有抗凋亡作用，并在更多的情况下阻止造血分化 成熟的细胞。我们预测白血病小鼠来源于MLL-AF4 ES细胞 将具有与人类MLL-AF4白血病相同的特定表型。我们会 对人类MLL-AF4白血病预后不良的假设进行评价 产生于对细胞凋亡的抵抗；在人类中，细胞凋亡发生在 生长因子剥夺或化疗后的预后白血病但不是 在MLL-AF4白血病中。我们修订了三个具体目标：(1)评估 假设融合基因是抗凋亡的，而AF4融合基因是 对这一效果至关重要。将利用类胚体研究分化 和造血系集落培养系统。条件MLL-AF4表达式 将开发系统来控制基因表达并允许 有活力的祖细胞。(2)评估以下假设： MLL-AF4融合基因具有细胞类型特异性。(3)研究MLL-AF4或 MLL-AF9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.