ROLE OF THE CHROMATIN REGULATOR, MLL, IN T CELL DEVELOPMENT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人类混合谱系白血病（MLL）基因最初是在急性白血病中频繁的染色体易位位点分离的。 MLL易位特别与婴儿白血病以及成人继发性白血病相关。 这种染色体易位导致由MLL的N-末端融合到许多鉴定的融合伴侣之一组成的融合癌基因的表达。 为了了解MLL融合蛋白致白血病的机制，确定MLL在体内的正常功能是至关重要的，特别是在可能代表MLL癌基因转化靶点的细胞类型中。 我们以前已经证明，小鼠MII是胚胎造血干细胞（HSC）发育所必需的，但其在成人造血过程中的重要性是未知的，由于纯合子MII损失的胚胎致死性。 使用诱导型敲除模型，我们将确定MII在造血系统中的正常作用。 这些研究将鉴定MII在以下方面的作用：1）骨髓内的HSC稳态，2）多能祖细胞功能和稳态，和3）使用谱系特异性cre重组酶菌株分化细胞类型。 研究将包括上述所有造血干细胞和祖细胞群体的表型和功能分析。 对在不存在MII的情况下解除调节的靶基因的鉴定的关注将建立一组候选基因，其既是潜在的直接靶标，又可能负责这些研究过程中发现的表型。 未来的研究将评估这些相同的靶基因和途径是否受到MII融合癌基因的干扰。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The human Mixed Lineage Leukemia (MLL) gene was originally isolated at the site of frequent chromosomal translocations in acute leukemia. MLL translocations are particularly associated with infant leukemia as well as secondary leukemias in adults. Such chromosomal translocations result in the expression of a fusion oncogene composed of the N-terminus of MLL fused to one of many identified fusion partners. To understand the mechanisms by which MLL fusion proteins are leukemogenic, it is critical to determine the normal function of MLL in vivo, particularly in the cell types that may represent the target for transformation by MLL oncogenes. We have previously demonstrated that murine Mll is essential for embryonic hematopoietic stem cell (HSC) development but its importance during adult hematopoiesis was unknown due to the embryonic lethality of homozygous Mll loss. Using an inducible knockout model we will determine the normal role of Mll in the hematopoietic system. These studies will identify roles for Mll in 1) HSC homeostasis within the bone marrow, 2) multipotent progenitor function and homeostasis, and 3) differentiating cell types using lineage-specific cre recombinase strains. Studies will include phenotypic and functional analysis of all hematopoietic stem and progenitor populations described above. A focus on the identification of target genes deregulated in absence of Mll will establish a set of candidate genes that are both potential direct targets and potentially responsible for the phenotypes discovered in the course of these studies. Future studies will assess whether these same target genes and pathways are perturbed by Mll fusion oncogenes.