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

描述（由申请人提供）：拟定工作重点关注B细胞淋巴瘤中的PI 3 K/Akt/Foxo 1轴。对许多生物体和细胞类型中的Foxo因子的研究已经导致了Foxo因子抑制细胞存活和增殖的观点。我们报道了Foxo 1在早期B细胞分化、IG基因重排、归巢和类转换重组中发挥非冗余作用。然而，我们没有发现在Foxo 1缺失的情况下B细胞增生或积累的证据，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）的测序工作已经注意到Foxo 1（而不是其他Foxo基因）在B细胞非霍奇金淋巴瘤（B-NHL）的大多数亚型中频繁突变。出乎意料的是，这些突变似乎是功能获得性突变，促进Foxo 1的核保留，从而持续激活Foxo 1转录程序。由于B-NHL来源于生发中心（GC）B细胞亚群，在拟议的工作中，我们将使用小鼠模型和人B淋巴瘤细胞系确定推定的功能获得性Foxo 1突变对GC B细胞分化和转化的影响。由于Foxo 1功能被认为是PI 3 K信号通路的主要转录靶点，因此这些发现将与以下研究直接相关： PI 3 K抑制剂在B细胞恶性肿瘤中的当前临床研究。

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.