T-cell receptor-driven lymphomagenesis in mice derived from a reprogrammed T cell

Abstract

The conversion of mature somatic cells into pluripotent stem cells, both by nuclear transfer and transduction with specific “reprogramming” genes, represents a major advance in regenerative medicine. Pluripotent stem cell lines can now be generated from an individual's own cells, facilitating the generation of immunologically acceptable stem cell-based therapeutics. Many cell types can undergo nuclear reprogramming, leading to the question of whether the identity of the reprogrammed cell of origin has a biological consequence. Peripheral blood, containing a mixture of T, B, NK, and myeloid cell types, represents one potential source of reprogrammable cells. In this study, we describe the unique case of mice derived from a reprogrammed T cell. These mice have prerearranged T-cell receptor (TCR) genes in all cells. Surprisingly, ≈50% of mice with prerearranged TCR genes develop spontaneous T cell lymphomas, which originate in the thymus. The lymphomas arise from developing T cells, and contain activated Notch1, similar to most human and mouse T-cell acute lymphoblastic lymphomas. Furthermore, lymphomagenesis requires the expression of both prerearranged TCRα and TCRβ genes, indicating a critical role for TCR signaling. Furthermore, inhibitors of multiple branches of TCR signaling suppress lymphoma growth, implicating TCR signaling as an essential component in lymphoma proliferation. The lymphomagenesis in mice derived from a reprogrammed T cell demonstrates the deleterious consequences of misregulation of the TCR rearrangement and signaling pathways and illustrates one case of cellular reprogramming where the identity of the cell of origin has profound consequences.

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

“…To investigate the contribution of tumor stroma to T-ALL growth, we used the LN3 murine model of T-ALL in which endogenous TCRαβ rearrangements promote spontaneous lymphomagenesis (21). Although the oncogenic lesions driving T-ALL in LN3 mice have not been elucidated, activation of NOTCH1 and NFAT were previously implicated (21).…”

“…To investigate the contribution of tumor stroma to T-ALL growth, we used the LN3 murine model of T-ALL in which endogenous TCRαβ rearrangements promote spontaneous lymphomagenesis (21). Although the oncogenic lesions driving T-ALL in LN3 mice have not been elucidated, activation of NOTCH1 and NFAT were previously implicated (21). Notch1 exon sequencing revealed nonsynonymous mutations in the heterodimerization or PEST domains in 64% (9/14) of primary LN3 tumors, with premature STOP codons in the PEST domains of 42% (6/14) of LN3 T-ALLs (Table S1).…”

How One Thing Led to Another

“…But, I should point out, it is now accepted to think of human B cell lymphomas using their immunoglobulin to bind to and proliferate in response to self-antigens (109-111)-or the receptor-mediated leukemogenesis hypothesis redux, only lacking reference to our 20-to 30-year-old studies. Our final paper in the field was recent-to show that mice derived by nuclear transfer from a lymph node T cell develop thymic lymphomas, but not if either the TCRα or the TCRβ is bred out; only those second-generation crosses with the original TCRαβ developed these lymphomas, and blocking TCR signaling blocked lymphoma proliferation (112).…”

RAG1/2 Knockout Pigs with Severe Combined Immunodeficiency

“…RAG1/2 knockout mice are both immunodeficient and characterized by the absence of mature B and T cells (7,8). Such mice are commonly used for immunological, inflammation, oncology, and stem cell transplantation studies (9)(10)(11)(12). Immunodeficient mice have also been used for the functional reconstitution of the human hematopoietic and immune systems by transplanting human hematopoietic stem cells (13).…”