Epigenetic manipulation of Leukemia

描述(由申请人提供)：HoxA9转录因子在人类急性髓系白血病(AML)中具有重要意义。HoxA9由涉及MLL1或Nup98(如MLLAf9、Nup98-HoxA9)的多个11号染色体易位激活。此外，通过HOX蛋白发出的信号与白血病干细胞的活性有关。在体外，MLL-AF9启动的白血病在半固体介质中产生集落，每个克隆在移植后能够启动白血病，因此至少包含一个白血病干细胞(LSC)。然而，由于白血病HOX信号的直接转录靶点还不清楚，HOX信号和LSC活性之间的分子联系也是未知的。我们的初步数据表明，HoxA9是通过microRNA基因传递信号的，抑制这些microRNA可以特异性地阻止HoxI介导的转化(通过MLL-AF9和Nup98-HoxA9)，并降低MLL-AF9 LSC的数量。我们推测，这些HOX-白血病信号的表观遗传成分可以扩大我们对LSC功能的分子机制的理解，并为AML的临床干预开辟新的途径。为此，我们建议定义模拟拮抗miR功能的生物修饰剂，并定义相关microRNA的靶标。这项拟议的研究有望剖析维持白血病干细胞表型的基因和蛋白质。 公共卫生相关性：急性髓系白血病是一种血液癌症，占美国癌症死亡人数的1.2%；然而，随着人口老龄化，这一比例预计会上升。此外，了解血细胞转化基础的研究应该会导致对白血病和异常造血的成功疗法的更深层次的理解和新的一代。

DESCRIPTION (provided by applicant): The HoxA9 transcription factor is of critical interest in human acute myeloid leukemia (AML). HoxA9 is oncogenically activated by multiple chromosome 11 translocations involving MLL1 or Nup98 (e.g. MLLAf9, Nup98-HoxA9). Moreover, signaling through Hox proteins has been linked to leukemia stem cell activity. In vitro, MLL-Af9-initiated leukemias generate colonies in semisolid media, and each colony is able to initiate leukemia upon transplantation and therefore contains at least one leukemia stem cell (LSC). However, because the direct transcriptional targets of leukemic Hox signaling are not well understood, the molecular link between Hox signaling and LSC activity is unknown. Our Preliminary Data indicate that HoxA9 signals through microRNA genes, and that inhibition of these microRNA specifically blocks Hoxmediated transformation (by MLL-Af9 and Nup98-HoxA9) and lowers MLL-Af9 LSC numbers. We hypothesize that these epigenetic components of Hox-leukemic signaling can be exploited to expand our understanding of molecular mechanisms of LSC function, and define new avenues for clinical intervention in AML. To this end, we propose to define biological modifiers that mimic the effect of antagonizing miR function, and to define targets of the relevant microRNA. The proposed research is expected to dissect genes and proteins that sustain the leukemic stem cell phenotype. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia, a cancer of the blood, accounts for 1.2% of cancer deaths in the United States; however, rates are expected to increase as the population ages. Moreover, research to understand the basis of blood cell transformation should lead to a deeper understanding, and the novel generation, of successful therapeutics for both leukemia and abnormal hematopoiesis.