Function of MTG16/ETO2 in acute leukemia

描述（由申请人提供）：与癌症（最常见的是造血系统恶性肿瘤）密切相关的染色体易位破坏了主调控基因。16号染色体上的髓系易位基因（MTG 16，也称为Eto 2）在急性髓系白血病（AML）中被t（16;21）染色体易位破坏，并且这种易位最常与治疗相关的AML相关。此外，在高达40%的最常见形式的乳腺癌中观察到MTG 16缺失。ETO/MTG 8（RUNX 1 T1）是一种密切相关的蛋白质，它被t（8;21）破坏，这是AML中最常见的染色体易位之一。该基因家族的第三个成员Mtgrl不直接受易位的影响，但位于20号染色体的一个区域，该区域在骨髓增生性疾病中经常缺失。MTG家族成员是核蛋白，其似乎起转录共阻遏物的作用，所述转录共阻遏物将调节DNA结合蛋白连接至组蛋白修饰酶以阻遏和/或沉默基因表达。为了开始了解依赖于Mtg 16的调控途径，我们从小鼠的生殖系中删除了该基因。Mtg 16缺失小鼠大多数是正常的，但表现出轻微的造血缺陷。然而，骨髓移植试验揭示了造血干细胞和祖细胞的功能的一个显着的缺陷，从Mtg 16-null小鼠的骨髓是无法保护致命的辐射受体小鼠和竞争性再增殖试验中的竞争力差。此外，Mtg 16-null干细胞和祖细胞在脾集落形成测定中完全缺陷。对于该提议重要的是，我们已经能够通过经由离体逆转录病毒转导重新表达Mtg 16来补充造血干细胞功能中的该缺陷。因此，我们有一个快速，强大的方法来评估Mtg 16在体内HSC中的作用。此外，我们已经创造了Mtgr 1缺陷小鼠，并发现这些小鼠在应激时也可能显示出结肠干细胞缺陷的迹象。最后，我们已经重新产生了Mtg 8-null嵌合小鼠，使得我们可以通过产生缺乏Mtg 16和Mtg 8或Mtgr 1的小鼠来遗传地剖析整个基因家族的作用。因此，我们将定义Mtg 16在造血干细胞中的作用，并确定这个关键调控基因家族在干细胞生物学和癌症中的功能。

DESCRIPTION (provided by applicant): The chromosomal translocations that are closely associated with cancer, most frequently hematopoietic malignancies, disrupt master regulatory genes. Myeloid Translocation Gene on chromosome 16 (MTG16, also known as Eto2) is disrupted by the t(16;21) chromosomal translocation in acute myeloid leukemia (AML), and this translocation is most commonly associated with therapy-related AML. In addition, deletion of MTG16 is observed in up to 40% of the most common form of breast cancer. ETO/MTG8 (RUNX1T1) is a closely related protein, which is disrupted by the t(8;21), which is one of the most frequent chromosomal translocations in AML. A third member of this gene family, Mtgrl, is not affected directly by translocations, but resides in a region of Chromosome 20 that is frequently deleted in myelo-proliferative disorders. MTG family members are nuclear proteins that appear to function as transcriptional co-repressors that link regulatory DNA binding proteins to histone modifying enzymes to repress and/or silence gene expression. To begin to understand the regulatory pathways that depend on Mtg16, we have deleted this gene from the germ line of mice. The Mtg16-null mice are mostly normal, but display mild hematopoietic defects. However, bone marrow transplantation assays revealed a dramatic defect in the function of hematopoietic stem cells and progenitor cells, as the bone marrow from Mtg16-null mice was unable to protect lethally irradiated recipient mice and poorly competed in competitive repopulation assays. Moreover, the Mtg16-null stem cells and progenitor cells were completely defective in spleen colony forming assays. Importantly for this proposal, we have been able to complement this defect in hematopoietic stem cell function by re- expression of Mtg16 via ex vivo retroviral transduction. Thus, we have a quick, robust method to assess Mtg16 action in HSCs in vivo. In addition, we have already created Mtgr1-deficient mice and found that these mice may also show signs of a stem cell defect in the colon upon stress. Finally, we have re- generated Mtg8-null chimeric mice, such that we can genetically dissect the action of the entire gene family by creating mice lacking Mtg16 and either Mtg8 or Mtgr1. Therefore, we will define the action of Mtg16 in the hematopoietic stem cell and determine the function of this key regulatory gene family in stem cell biology and cancer.