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Abstract SL/Kh mice develop a high frequency of retrovirally-induced pre-B lymphomas at 3-6 months of age. They also exhibit an abnormal transient expansion of pre-B cells in the bone marrow, although the relevance of this expansion for lymphomagenesis has remained unclear. Here, we use a dual approach that combines pathology with flow cytometry to more fully characterize the nature and origin of SL/Kh lymphomas. Unexpectedly, our studies showed that SL/Kh lymphomas arise from a rare population of pro/pre-B cells in the thymus. We also identified a 10-fold reduction in Notch1 expression in SL/Kh thymic T cells that is associated with a block in early T cell development, a reduction in the number of thymic T cells with age, and an expansion of thymic pro/pre-B cells. This phenotype is consistent with previous studies showing that Notch1 signaling is essential for lymphoid progenitors to undergo T cell commitment and for suppressing B cell development in the thymus. We propose that this developmental defect provides a niche for early B cells to accumulate in the thymus, which, when combined with subsequent retroviral insertional mutagenesis, results in the induction of pre-B lymphomas that originate in the thymus. This is also consistent with our analysis of the genes insertionally mutated in SL/Kh lymphomas, which shows that many function in signaling pathways such as JAK/STAT and RAS/MAPK/ERK that are commonly deregulated in B-cell lymphomas. Primary human mediastinal large B-cell lymphoma (MLBCL) is another lymphoma that is derived from thymic B cells, although virtually nothing is known about the cause of this rare disease. Our studies provide new insights into an underappreciated class of B-cell lymphomas and a mouse model for the study of MLBCL.