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

基本信息

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
项目类别：
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&apos s lymphoma mouse model mutant programs public health relevance response

项目摘要

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）：拟议的工作集中于B细胞淋巴瘤中的PI3K/AKT/FOXO1轴。在许多生物体和细胞类型中的FOXO因素上的工作已导致FOXO因素因素因素抑制细胞的存活和增殖。我们报告说，FOXO1在早期B细胞分化，IG基因重排，归巢和类开关重组中发挥了非冗余作用。但是，我们没有发现在没有FOXO1的情况下B细胞增生或积累的证据，反对抑制肿瘤的作用。实际上，最近报道了卵泡淋巴瘤（FL），伯基特淋巴瘤和弥漫性大B细胞淋巴瘤（DLBCL）的测序努力指出，在大多数B细胞非霍奇金淋巴瘤（B-NHL）的大多数亚型中，FOXO1（而不是其他FOXO基因）经常突变。出乎意料的是，这些突变似乎是促进FOXO1的核保留率，从而持续激活FOXO1转录程序。由于B-NHL源自生殖中心（GC）B细胞子集，因此在拟议的工作中，我们将使用小鼠模型和人类B淋巴瘤线来确定推定功能的FORCO1突变在GC B细胞分化和转化中的影响。由于FOXO1函数被认为是PI3K信号通路的主要转录目标，因此这些发现将与 B细胞恶性肿瘤中PI3K抑制剂的当前临床研究。