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

描述（由申请人提供）：拟开展的工作重点是B细胞淋巴瘤中的PI3K/Akt/Foxo1轴。对许多生物体和细胞类型中Foxo因子的研究已经导致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、归巢和类开关重组中发挥非冗余作用。然而，我们没有发现在缺乏Foxo1的情况下B细胞增生或积累的证据，这就反驳了Foxo1的肿瘤抑制作用。事实上，最近报道的滤泡性淋巴瘤（FL）、伯基特淋巴瘤（Burkitt’s lymphoma）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突变，促进Foxo1的核保留，从而持续激活Foxo1转录程序。由于B- nhl来源于生发中心（GC） B细胞亚群，在本研究中，我们将利用小鼠模型和人B淋巴瘤系来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点，这些发现将直接与

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.