EKLF (KLF1): A Potential Tumor Suppressor?

EKLF (KLF1)：潜在的肿瘤抑制剂？

• 批准号: 7901246
• 负责人: JAMES J BIEKER
• 金额: $ 22.12万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901246
• 关键词: Acute Myelocytic Leukemia; Address; Antibodies; Attenuated; Biological Markers; Bone Marrow; Bone Marrow Cells; Cell Cycle; Cell Line; Cell Proliferation; Cells; Characteristics; Erythroid; Evaluation; Family member; Future; Genetic; Genetic Transcription; Grant; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; High Pressure Liquid Chromatography; Human; Lead; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Megakaryocytopoieses; Modification; Molecular; Mutate; Nature; Patients; Play; Property; Proteins; Reagent; Repression; Role; Sampling; Series; Testing; Time; TimeLine; Tissues; Tumor Suppressor Proteins; Variant; Zinc Fingers; base; cancer cell; clinically relevant; design; erythroid Kruppel-like factor; inhibitor/antagonist; leukemia; leukemogenesis; mutant; novel; prevent; public health relevance; research study; transcription factor

DESCRIPTION (provided by applicant): Functional inactivation of tumor suppressors plays an important role in malignancy. Many tumor suppressors normally interface with the cell cycle machinery and form part of its exquisite control mechanism. Loss of these controls can lead to unrestricted proliferation and impaired differentiation, both of which are characteristic of acute myeloid leukemia. EKLF (Erythroid Kr¿ppel Like Factor; KLF1) is a zinc finger hematopoietic transcription factor that is absolutely critical for the erythroid lineage. Our recent studies have also revealed an unexpected role of EKLF as an inhibitor of megakaryopoiesis, suggesting a novel function of this transcription factor in lineage commitment during hematopoiesis. EKLF inhibits cellular proliferation and induces endogenous expression of the cell cycle inhibitor p21. As a result, we hypothesize that human EKLF may play a role in hematopoietic malignancy consistent with that of a tumor suppressor, and this exploratory proposal will evaluate this idea by two aims. In the first, we will use an antibody that recognizes human EKLF protein to analyze human normal and leukemic tissue and cell samples for the presence/absence of EKLF protein, and determine whether its expression correlates with a specific malignant subtype. In the second, the sequence of the complete human EKLF transcription unit will be compared between normal bone marrow and a number of human leukemic cell lines and malignant primary cells to see if EKLF is mutated in any of these lines. Functional tests of any variant EKLF proteins that are discovered will follow both of these aims and will also provide a basis for future experiments that extend beyond the timeline of this exploratory grant. Successful attainment of the aims in this proposal will determine whether mutated EKLF/KLF1 plays a role in leukemia, thus providing a novel biomarker, and will direct future applicability towards the most clinically relevant samples. PUBLIC HEALTH RELEVANCE: Tumor suppressors play an important role in preventing malignancy. EKLF, a critical zinc finger hematopoietic transcription factor, has antiproliferative properties consistent with that of a tumor suppressor. As a result, our test hypothesis is that EKLF is playing an unappreciated role as a tumor suppressor, and that its dysregulation can contribute or lead to human leukemia.

描述（由申请人提供）：肿瘤抑制因子的功能性失活在恶性肿瘤中起着重要作用。许多肿瘤抑制因子通常与细胞周期机制相互作用，并形成其精致控制机制的一部分。失去这些控制可能导致增殖不受限制和分化受损，这两者都是急性髓系白血病的特征。 EKLF（红细胞 Kr¿ppel 样因子；KLF1）是一种锌指造血转录因子，对于红细胞谱系绝对至关重要。我们最近的研究还揭示了 EKLF 作为巨核细胞生成抑制剂的意外作用，表明该转录因子在造血过程中的谱系定型中具有新功能。 EKLF 抑制细胞增殖并诱导细胞周期抑制剂 p21 的内源表达。因此，我们假设人类 EKLF 可能在造血系统恶性肿瘤中发挥与肿瘤抑制因子一致的作用，并且该探索性提案将通过两个目标评估这一想法。 首先，我们将使用识别人类 EKLF 蛋白的抗体来分析人类正常和白血病组织和细胞样本中是否存在 EKLF 蛋白，并确定其表达是否与特定的恶性亚型相关。第二步，将在正常骨髓和许多人类白血病细胞系和恶性原代细胞之间比较完整的人类 EKLF 转录单元的序列，以查看 EKLF 在这些细胞系中是否发生突变。对发现的任何 EKLF 蛋白变体的功能测试都将遵循这两个目标，并且还将为超出本次探索性资助的时间范围的未来实验提供基础。 成功实现该提案中的目标将确定突变的 EKLF/KLF1 是否在白血病中发挥作用，从而提供一种新型生物标志物，并将指导未来对临床最相关样本的适用性。 公共卫生相关性：肿瘤抑制因子在预防恶性肿瘤方面发挥着重要作用。 EKLF 是一种关键的锌指造血转录因子，具有与肿瘤抑制因子一致的抗增殖特性。因此，我们的测试假设是 EKLF 作为肿瘤抑制因子发挥着未被充分认识的作用，并且其失调可能导致或导致人类白血病。