NR4A Nuclear Receptor Function in Leukemia

描述（由申请人提供）：本项目的总体目标是阐明核受体nor-1和nur-77作为肿瘤抑制因子发挥作用以预防髓性白血病发展的机制。Nur 77和nor-1是核受体转录因子NR 4A亚家族的成员。NR 4A受体具有高度同源的氨基酸序列，并且可以与常见的顺式作用DNA元件相互作用以调节重叠的靶基因。与大多数核受体不同，NR 4A亚家族成员不是配体激活的，并且可以作为组成型活性转录因子发挥作用。此外，它们是立即早期基因的产物，其表达和活性响应于多种细胞外促有丝分裂、凋亡和分化刺激以细胞特异性方式调节。为了阐明NR 4A受体的基本生理作用，我们已经产生了无效突变小鼠，其中这些蛋白质的表达已被消融。目前的建议是基于我们最近的发现，即nur 77和nor-1缺陷的小鼠迅速发展致命的髓性白血病，其在其发展的潜伏期中是nor-1/nur 77基因剂量依赖性的，并且最接近于慢性髓性白血病（CML）的急性期。我们假设nor 1和nur 77是最有可能在造血干细胞（HSC）或下游髓系祖细胞中起作用的重要肿瘤抑制转录因子，并通过与细胞周期组分的通讯来调节自我更新，增殖和细胞存活之间的平衡。我们进一步假设nor 1/nur 77的失活可能在慢性骨髓增生性疾病进展到急性期中起关键作用。为了验证这一假设，我们将1）继续检查nor 1/nur 77无效突变小鼠中髓性白血病起始和进展的细胞机制，2）鉴定控制骨髓细胞发育的nor 1/nur 77依赖性分子遗传信号传导途径，3）确定nor 1/nur 77的缺失是否与BCR-ABL致癌信号传导协同作用，以驱动CML小鼠模型的急性期进展，和4）确定NOR 1和Nur 77对骨髓祖细胞的转基因靶向是否足以挽救NOR 1/Nur 77缺失小鼠中的白血病表型。

DESCRIPTION (provided by applicant): The overall objective of this project is to elucidate the mechanisms by which the nuclear receptors nor-1 and nur77 function as tumor suppressors to prevent the development of myeloid leukemia. Nur77 and nor-1 are members of the NR4A subfamily of nuclear receptor transcription factors. NR4A receptors have highly homologous amino acid sequences and can interact with common cis-acting DNA elements to regulate overlapping target genes. Unlike most nuclear receptors, NR4A subfamily members are not ligand activated and can function as constitutively active transcription factors. In addition, they are products of immediate early genes whose expression and activity are regulated in a cell specific manner in response to a variety of extracellular mitogenic, apoptotic and differentiative stimuli. In order to elucidate the essential physiological roles of NR4A receptors, we have generated null mutant mice in which the expression of these proteins has been ablated. The current proposal is based on our recent discovery that mice deficient in both nur77 and nor-1 develop rapidly lethal myeloid leukemia that is nor1/nur77 gene dosage dependent in its latency of development and most closely resembles the acute phase of chronic myeloid leukemia (CML). We hypothesize that nor1 and nur77 are essential tumor suppressor transcription factors operating most likely in hematopoietic stem (HSCs) or downstream myeloid progenitor cells and exert their effects by communication with cell cycle components to regulate the balance between serf renewal, proliferation and cell survival. We further hypothesize that inactivation of nor1/nur77 may play a key role in driving progression of chronic myeloproliferative disease to acute phase. To test this hypothesis, we will 1) continue to examine the cellular mechanisms of initiation and progression of myeloid leukemia in nor1/nur77 null mutant mice, 2) identify the nor1/nur77 dependent molecular genetic signaling pathways that control myelopoietic cell development, 3) determine whether loss of nor1/nur77 cooperates with BCR-ABL oncogenic signaling to drive acute phase progression in a mouse model of CML, and 4) determine whether transgenic targeting of nor1 and nur77 to myeloid progenitor cells is sufficient to rescue the leukemic phenotype in nor1/nur77 null mice.