Characterization of a non-canonical role for Foxo1 in B cell lymphoma

Foxo1 在 B 细胞淋巴瘤中的非典型作用的表征

• 批准号: 8692377
• 负责人: ROBERT C RICKERT
• 金额: $ 25.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692377
• 关键词: Accounting; Amino Acids; Apoptosis; B cell differentiation; B lymphoid malignancy; B-Cell Lymphomas; B-Cell Neoplasm; B-Cell NonHodgkins Lymphoma; B-Lymphocyte Subsets; B-Lymphocytes; Burkitt Lymphoma; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Clinical Research; Clinical Trials; Disease; Exclusion; Follicular Lymphoma; Gene Expression Profile; Gene Rearrangement; Gene Targeting; Generations; Genes; Genomics; Homing; Human; Hyperplasia; Immunoglobulin Class Switching; Immunoglobulin Genes; Immunoglobulin Switch Recombination; Lymphomagenesis; Mediating; Methionine; Molecular; Mus; Mutate; Mutation; Nuclear; Organism; Pathway interactions; Peripheral; Phenocopy; Phosphorylation Site; Property; Prospective Studies; Proteins; Recurrence; Reporting; Role; Signal Pathway; Site; Structure of germinal center of lymph node; Transcriptional Regulation; Translation Initiation; Tumor Suppressor Proteins; Work; Xenograft procedure; cell transformation; cell type; gain of function; gain of function mutation; inhibitor/antagonist; insight; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; mutant; programs; public health relevance; response

DESCRIPTION (provided by applicant): The proposed work focuses on the PI3K/Akt/Foxo1 axis in B cell lymphoma. Work on the Foxo factors in numerous organisms and cell types have led to the view that Foxo factors inhibit cell survival and proliferation. We reported that Foxo1 exerts a nonredundant role in early B cell differentiation, Ig gene rearrangement, homing and class switch recombination. However, we found no evidence of B cell hyperplasia or accumulation in the absence of Foxo1, arguing against a tumor suppressor role. Indeed, recently reported sequencing efforts in follicular lymphoma (FL), Burkitt's lymphoma and diffuse large B cell lymphoma (DLBCL) have noted that Foxo1 (and not other Foxo genes) is frequently mutated in most subtypes of B cell non-Hodgkin's lymphoma (B-NHL). Unexpectedly, these mutations appear to be gain-of-function mutations that promote nuclear retention of Foxo1 and thus sustained activation of the Foxo1 transcriptional program. Since B-NHL is derived from the germinal center (GC) B cell subset, in the proposed work we will determine the impact of the putative gain-of-function Foxo1 mutations in GC B cell differentiation and transformation using mouse models and human B lymphoma lines. As Foxo1 function is thought to be the primary transcriptional target of the PI3K signaling pathway, these findings will be of direct relevance to current clinical studies of PI3K inhibitors in B cell malignancies.

描述（由申请人提供）：拟议的工作重点是 B 细胞淋巴瘤中的 PI3K/Akt/Foxo1 轴。对多种生物体和细胞类型中 Foxo 因子的研究得出了 Foxo 因子抑制细胞存活和增殖的观点。我们报道 Foxo1 在早期 B 细胞分化、Ig 基因重排、归巢和类别转换重组中发挥非冗余作用。然而，我们没有发现在 Foxo1 缺失的情况下 B 细胞增生或积累的证据，从而反对肿瘤抑制作用。事实上，最近报道的滤泡性淋巴瘤 (FL)、伯基特淋巴瘤和弥漫性大 B 细胞淋巴瘤 (DLBCL) 的测序工作表明，Foxo1（而不是其他 Foxo 基因）在大多数 B 细胞非霍奇金淋巴瘤 (B-NHL) 亚型中经常发生突变。出乎意料的是，这些突变似乎是功能获得性突变，可促进 Foxo1 的核保留，从而持续激活 Foxo1 转录程序。由于 B-NHL 源自生发中心 (GC) B 细胞亚群，因此在拟议的工作中，我们将使用小鼠模型和人 B 淋巴瘤系确定假定的功能获得性 Foxo1 突变对 GC B 细胞分化和转化的影响。由于 Foxo1 功能被认为是 PI3K 信号通路的主要转录靶标，因此这些发现将与 目前 PI3K 抑制剂治疗 B 细胞恶性肿瘤的临床研究。