EKLF (KLF1): A Potential Tumor Suppressor?

描述(申请人提供)：肿瘤抑制基因的功能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连，并形成其精细控制机制的一部分。失去这些控制可导致不受限制的增殖和分化受损，这两者都是急性髓系白血病的特征。EKLF是一种锌指造血转录因子，在红系血统中起着至关重要的作用。我们最近的研究还揭示了EKLF作为巨核细胞生成抑制因子的一个意想不到的作用，表明该转录因子在造血过程中的谱系承诺中具有新的功能。EKLF抑制细胞增殖，诱导细胞周期抑制因子p21的内源性表达。因此，我们假设人类EKLF可能在血液系统恶性肿瘤中发挥与肿瘤抑制因子一致的作用，这一探索性建议将通过两个目标来评估这一想法。首先，我们将使用一种识别人类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。在第二项研究中，我们将比较正常骨髓、一些人类白血病细胞系和恶性原代细胞的完整人类EKLF转录单位的序列，以确定EKLF在这些细胞系中是否发生突变。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，并将为未来的实验提供基础，这些实验将延伸到这次探索性拨款的时间表之外。成功实现这项建议的目标将决定突变的EKLF/KLF1是否在白血病中发挥作用，从而提供一个新的生物标记物，并将指导未来的应用于最具临床相关性的样本。 公共卫生相关性：肿瘤抑制物在预防恶性肿瘤方面发挥着重要作用。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作为一种肿瘤抑制因子正在扮演着一个未被认识的角色，它的失调可能导致或导致人类白血病。

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.