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（由申请方提供）：肿瘤抑制因子的功能失活在恶性肿瘤中起重要作用。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。这些控制的丧失可导致不受限制的增殖和受损的分化，这两者都是急性髓性白血病的特征。EKLF（红细胞Kr <$ppel样因子; KLF 1）是一种锌指造血转录因子，对红细胞系至关重要。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想不到的作用，表明这种转录因子在造血过程中的谱系定型中具有新的功能。EKLF抑制细胞增殖并诱导细胞周期抑制剂p21的内源性表达。因此，我们假设人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，并且这个探索性的建议将通过两个目标来评估这个想法。 首先，我们将使用识别人EKLF蛋白的抗体来分析人正常和白血病组织和细胞样品中EKLF蛋白的存在/不存在，并确定其表达是否与特定的恶性亚型相关。在第二项研究中，将在正常骨髓和许多人白血病细胞系和恶性原代细胞之间比较完整的人EKLF转录单位的序列，以观察EKLF是否在这些细胞系中发生突变。对发现的任何变异EKLF蛋白的功能测试都将遵循这两个目标，也将为未来的实验提供基础，这些实验将超出本探索性资助的时间轴。 成功实现本提案中的目标将确定突变的EKLF/KLF 1是否在白血病中发挥作用，从而提供一种新的生物标志物，并将指导未来对最临床相关样本的适用性。 公共卫生相关性：肿瘤抑制剂在预防恶性肿瘤中发挥重要作用。EKLF是一种重要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，我们的检验假设是，EKLF作为肿瘤抑制因子发挥着未被重视的作用，其失调可能导致或导致人类白血病。