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

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)-1α 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-1α in chronic lymphocytic leukemia (CLL) development in vivo. To this end, we crossed the CLL mouse model Eµ-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-1α 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.

Hypoxic stress and hypoxia-inducible factors in leukemias

“…This genetic experiment is particularly puzzling in view of the significant upregulation of hypoxic gene signatures that was reported in leukemic cells from Eμ-TCL1 mice ( 110 ), thus confirming data obtained by other laboratories of augmented hypoxia signaling in CLL ( 65 – 67 ). However, HIF1α knock-out did not affect the transcriptional program of Eμ-TCL1 leukemic cells ( 110 ). Therefore, the authors of this paper speculated that compensatory mechanisms may occur that render HIF1α inactivation of no consequence.…”

“…Similar head-scratching results have been recently published for CLL, where it was shown that knock-out of the HIF1α gene in the Eμ-TCL1 mouse model did not impact CLL progression or increase mice survival, suggesting that HIF1α is not essential for CLL leukemogenesis ( 110 ). This genetic experiment is particularly puzzling in view of the significant upregulation of hypoxic gene signatures that was reported in leukemic cells from Eμ-TCL1 mice ( 110 ), thus confirming data obtained by other laboratories of augmented hypoxia signaling in CLL ( 65 – 67 ). However, HIF1α knock-out did not affect the transcriptional program of Eμ-TCL1 leukemic cells ( 110 ).…”

Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses

“…Similar results were obtained with the Eμ- TCL1 (TCL1) CLL murine model (GSE175564, ref. 21 ; vs. WT B cells from C57BL/6 mouse; Fig. 1F and G ) as Cd9 , Rab3b , and Rab31 were upregulated (Fig.…”