B cells are indispensable for normal immune surveillance systems and their dysfunction leads to the development of autoimmune diseases and B cell malignancies. While progress has been made in elucidating the molecular events underlying normal B cell development, further research is required to address the limitations of current therapeutic strategies. The objective of this application is to further clarify the role of the proto-oncogene Leukemia/lymphoma Related Factor (LRF, also known as Pokemon) in normal and malignant B cell development. This will be done by employing a series of mutant mouse models and molecular approaches. This proposal was formulated based on our findings that: 1) LRF acts as a proto-oncogene and is highly expressed in Non-Hodgkin Lymphoma tissues: 2) LRF opposes Notch function at the hematopoietic stem cell (HSC) level and is indispensable for normal B cell development in the bone marrow and 3) formation of Germinal Centers (GCs), where critical molecular events for both normal (antibody diversification) and malignant (oncogenic transformation) B cell function take place, is severely impaired in B cell specific LRF conditional knockout (KO) mice. The central hypothesis of the application is that LRF is required for the maintenance of normal and malignant mature B cells and thus represents a potential therapeutic target for subsets of B cell lymphomas as well as autoimmune diseases. The rationale for the proposed research is that it is expected to provide a greater understanding of normal and malignant B cell development, facilitating the advancement of novel therapeutic strategies. Guided by strong preliminary data, we will test our hypothesis by pursuing two specific aims: 1) Determine the role of LRF in normal and malignant mature B cell development in vivo;2) Identify the molecular mechanisms by which LRF functions in GCB cells. Under the first aim, we will determine the role of LRF in B cells by employing both loss of function (LRF conditional KO) and gain of function (LRF tissue specific knockin) mice models.
Under aim #2, we will identify key transcription modifiers that interact with LRF via a proteomic approach. The proposed project is innovative because it takes advantage of unique in vivo mouse models (aim #1), capitalizing on underlying molecular mechanisms, and employs novel genome-wide molecular approaches (aim #2). These studies will have an important positive impact by increasing our understanding of normal and malignant B cell development, as well as by facilitating the development of new therapeutic strategies for B cell malignancies and autoimmune diseases.
The proposed research is relevant to public health as elucidation of the molecular mechanism underlining normal B cell development will expedite the development of innovative therapeutic strategies targeting B cell- associated malignancies as well as auto-immune diseases.
|Masuda, Takeshi; Wang, Xin; Maeda, Manami et al. (2016) Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 351:285-9|
|Canver, Matthew C; Bauer, Daniel E; Dass, Abhishek et al. (2014) Characterization of genomic deletion efficiency mediated by clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 nuclease system in mammalian cells. J Biol Chem 289:21312-24|
|Bohn, Olga; Maeda, Takahiro; Filatov, Alexander et al. (2014) Utility of LRF/Pokemon and NOTCH1 protein expression in the distinction between nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma. Int J Surg Pathol 22:6-11|
|Chen, Caiyong; Garcia-Santos, Daniel; Ishikawa, Yuichi et al. (2013) Snx3 regulates recycling of the transferrin receptor and iron assimilation. Cell Metab 17:343-52|
|Lee, Sung-Uk; Maeda, Manami; Ishikawa, Yuichi et al. (2013) LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance. Blood 121:918-29|
|Lunardi, Andrea; Guarnerio, Jlenia; Wang, Guocan et al. (2013) Role of LRF/Pokemon in lineage fate decisions. Blood 121:2845-53|
|Zhang, Bin; Ho, Yin Wei; Huang, Qin et al. (2012) Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21:577-92|
|Tsuji-Takechi, Kaori; Negishi-Koga, Takako; Sumiya, Eriko et al. (2012) Stage-specific functions of leukemia/lymphoma-related factor (LRF) in the transcriptional control of osteoclast development. Proc Natl Acad Sci U S A 109:2561-6|
|Lee, Sung-Uk; Maeda, Takahiro (2012) POK/ZBTB proteins: an emerging family of proteins that regulate lymphoid development and function. Immunol Rev 247:107-19|
|Sakurai, Nagisa; Maeda, Manami; Lee, Sung-Uk et al. (2011) The LRF transcription factor regulates mature B cell development and the germinal center response in mice. J Clin Invest 121:2583-98|