The Tumor Microenvironment-Dependent Transcription Factors AHR and HIF-1α Are Dispensable for Leukemogenesis in the Eμ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia

Simple Summary: Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, mostly affecting the elderly. The survival of leukemic cells depends on multiple soluble factors and on the stimulation of the BCR signaling pathway. Microenvironment-dependent transcription factors also contribute to CLL biology. Here, we generated new transgenic murine conditional knock-out models of CLL to study the role of the two transcription factors HIF-1 alpha and AHR. Unexpectedly, we observed that both factors are dispensable for leukemia development in these models. Abstract: Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the elderly and is characterized by the accumulation of mature B lymphocytes in peripheral blood and primary lymphoid organs. In order to proliferate, leukemic cells are highly dependent on complex interactions with their microenvironment in proliferative niches. Not only soluble factors and BCR stimulation are important for their survival and proliferation, but also the activation of transcription factors through different signaling pathways. The aryl hydrocarbon receptor (AHR) and hypoxia-inducible factor (HIF)-1 alpha are two transcription factors crucial for cancer development, whose activities are dependent on tumor microenvironment conditions, such as the presence of metabolites from the tryptophan pathway and hypoxia, respectively. In this study, we addressed the potential role of AHR and HIF-1 alpha in chronic lymphocytic leukemia (CLL) development in vivo. To this end, we crossed the CLL mouse model E mu-TCL1 with the corresponding transcription factor-conditional knock-out mice to delete one or both transcription factors in CD19+ B cells only. Despite AHR and HIF-1 alpha being activated in CLL cells, deletion of either or both of them had no impact on CLL progression or survival in vivo, suggesting that these transcription factors are not crucial for leukemogenesis in CLL.

Automated summary

In this study, new transgenic murine conditional knock-out models of CLL were generated to investigate the role of the transcription factors HIF-1 alpha and AHR. Surprisingly, it was observed that both factors are dispensable for leukemia development in these models.