Role of PMAIP1 (NOXA) and FOXO1 in interleukin-21 mediated apoptosis in mantle cell lymphoma

• Applicant: Dr. Ina Lackner
• Subject Area: Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 529007119

Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin’s B cell lymphoma. MCL is a lymphoid neoplasm, characterized by an abnormal proliferation of mature B lymphocytes, derived from the mantle zone of lymphoid follicles. MCL usually shows an aggressive clinical course with comparatively short response to chemotherapy, frequent relapses, and a median survival of 5-7 years. The pleiotropic cytokine interleukin-21 (IL-21) shows a remarkably broad range of actions and is crucially involved in B cell development, differentiation, and homeostasis. One special feature of IL-21 is its pro-apoptotic effect on resting and activated B cells. Besides its regulatory functions, IL-21 is furthermore considered as a potential immunotherapeutic agent for cancer and B cell lymphomas, including MCL. However, the underlying molecular mechanisms of IL-21-induced apoptosis in MCL are poorly understood. Preliminary experiments from our group with Mino cells, an MCL cell line, identified PMAIP1 (NOXA) and FOXO1 as mediators of IL-21 induced apoptosis in MCL. PMAIP1 (NOXA) and FOXO1 have already been described in the context of MCL. However, a link between IL-21 and PMAIP1 (NOXA) or FOXO1 has not been demonstrated, and the role of PMAIP1 (NOXA) and FOXO1 in IL-21 mediated apoptosis in MCL is unknown. Moreover, the effect of IL-21, PMAIP1 (NOXA) and FOXO1 in other B cell populations, such as B1a cells, which may give rise to the development of MCL, are unknown. In addition, a basic phenotype of B cells in Pmaip1- and Foxo1-deficient mice has not been described yet. Thus, the aim of the proposed project is to precisely examine the role of PMAIP1 (NOXA) and FOXO1 in IL-21-mediated apoptosis in MCL as well as in other primary normal B cell populations such as B1a cells, and to further characterize the phenotype of Pmaip1- and Foxo1-deficient mice. By using a panel of MCL cell lines and by a specific CRISPR-Cas9 deletion of PMAIP1 (NOXA) and FOXO1 in these cells, the role of these two genes in IL-21-mediated apoptosis in MCL will be revealed. Also, the role of these two genes in IL-21-mediated cell death will be unveiled in primary murine and human B and B1a cells. Using Foxo1 conditional knock out and Pmaip1 knock out mice, their B cell subpopulations and their phenotype will be characterized. By using molecular biological methods in combination with innovative Next-Generation sequencing techniques and genetically modified animals, the proposed project will shed light on IL-21-mediated apoptosis in B cells and MCL as well as on its involved genes. Uncovering the molecular pathways of IL-21-induced apoptosis in MCL will offer novel and promising therapeutic treatment strategies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Warren J. Leonard