The Role of the IRF4-NOTCH2 Interplay in B-Cell Development and Malignancy

• Applicant: Dr. Maja Milanovic
• Subject Area: Cell Biology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268806633

The development of B lymphocytes is tightly controlled by the coordinated expression of master transcriptional regulators. Aberrant expression of these regulators due to genetic alterations can disrupt ordered B-cell development and contribute to oncogenic transformation. The transcription factor interferon regulatory factor-4 (IRF4) has been identified as a potential tumor suppressor in B-cell chronic lymphocytic leukemia (CLL), a malignancy of quiescent mature B cells. Towards understanding the function of IRF4 in B cells, the host laboratory has recently obtained evidence that IRF4 controls the migration and homing properties of mature B cells within the lymphoid tissues. Thus, it has been observed that the inducible deletion of the irf4 gene in vivo led to an accumulation of IRF4-deficient B cells in the lymphoid microenvironment of the marginal zone. Notably, NOTCH2 signaling was found to be hyperactivated in IRF4-deficient B cells, and inhibition of NOTCH2 signaling by a therapeutic monoclonal antibody led to a rapid disintegration of the marginal zone. These results are likely to be relevant for CLL, since published evidence suggests that NOTCH2 is constitutively active in CLL tumor cells. The underlying hypothesis is that alterations in the balance of the transcriptional network established by IRF4 and NOTCH2 may disrupt the normal migration and homing properties of B cells and thereby contribute to lymphomagenesis by aberrantly positioning transformed B cells in a lymphoid microenvironment that supports survival.Here I propose to elucidate the molecular mechanism by which IRF4 regulates NOTCH2 activation in B cells. In addition, I will determine the biological program controlled by NOTCH2 in IRF4-deficient B cells by performing a genome-wide identification of transcriptional targets. Finally, I will investigate the effects of a NOTCH2-inhibitory antibody on CLL cell phenotype and function in in vitro assays that mimic the CLL proliferation center microenvironment. Elucidating the functional interplay between IRF4 and NOTCH2 in normal B-cell physiology and its disruption in malignancy has the potential to provide the basis for developing innovative therapeutic strategies targeted at CLL and splenic marginal zone B-cell lymphoma, where NOTCH2 hyperactivation has been associated with tumor-promoting roles.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Ulf Klein