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.

Public Health Relevance

Completion of the proposed work will provide fundamental and mechanistic insight into the transcriptional control of germinal center B cell differentiation and transformation, and thus the molecular underpinnings of B cell non-Hodgkin's lymphoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA179302-02
Application #
8920519
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Howcroft, Thomas K
Project Start
2014-09-05
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037