RelB-Dependent Stromal Cells Promote T-Cell Leukemogenesis

Background: The Rel/NF-kappa B transcription factors are often activated in solid or hematological malignancies. In most cases, NF-kappa B activation is found in malignant cells and results from activation of the canonical NF-kappa B pathway, leading to RelA and/or c-Rel activation. Recently, NF-kappa B activity in inflammatory cells infiltrating solid tumors has been shown to contribute to solid tumor initiation and progression. Noncanonical NF-kappa B activation, which leads to RelB activation, has also been reported in breast carcinoma, prostate cancer, and lymphoid leukemia. Methodology/Principal Findings: Here we report a novel role for RelB in stromal cells that promote T-cell leukemogenesis. RelB deficiency delayed leukemia onset in the TEL-JAK2 transgenic mouse model of human T acute lymphoblastic leukemia. Bone marrow chimeric mouse experiments showed that RelB is not required in the hematopoietic compartment. In contrast, RelB plays a role in radio-resistant stromal cells to accelerate leukemia onset and increase disease severity. Conclusions/Significance: The present results are the first to uncover a role for RelB in the crosstalk between non-hematopoietic stromal cells and leukemic cells. Thus, besides its previously reported role intrinsic to specific cancer cells, the noncanonical NF-kappa B pathway may also play a pro-oncogenic role in cancer microenvironmental cells.