Epigenetic manipulation of Leukemia

描述（由申请人提供）：HoxA9转录因子在人类急性髓性白血病（AML）中具有重要意义。HoxA9通过涉及MLL1或Nup98（如MLLAf9， Nup98-HoxA9）的多个11号染色体易位被致癌激活。此外，通过Hox蛋白传递的信号与白血病干细胞活性有关。在体外，mll - af9引发的白血病在半固体培养基中产生菌落，每个菌落能够在移植时引发白血病，因此包含至少一个白血病干细胞（LSC）。然而，由于白血病Hox信号的直接转录靶点尚不清楚，Hox信号和LSC活性之间的分子联系尚不清楚。我们的初步数据表明，HoxA9通过microRNA基因传递信号，抑制这些microRNA特异性地阻断了HoxA9介导的转化（MLL-Af9和Nup98-HoxA9），并降低了MLL-Af9的LSC数量。我们假设hox -白血病信号的这些表观遗传成分可以用来扩展我们对LSC功能的分子机制的理解，并为AML的临床干预确定新的途径。为此，我们建议定义模拟miR拮抗作用的生物修饰剂，并确定相关microRNA的靶点。这项拟议的研究有望解剖维持白血病干细胞表型的基因和蛋白质。

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.