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Abstract
Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs), creating a preleukemic stem cell (PLSC). Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC). Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM), but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus. We studied PLSC linked to thymic lymphomas. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Following BM transplantation, we found that MSH2-/- BM cells from young mice are able to fully reconstitute multiple hematopoietic lineages of lethally irradiated wild-type recipients. However, all recipients developed thymic lymphomas within three and four months post transplantation. Transplantation of different fractions of BM cells or thymocytes from young health MSH2-/- mice showed that an HSC enriched fraction always reconstituted hematopoiesis followed by lymphoma development. In addition, lymphomas did not occur in thymectomized recipients of MSH2-/- BM. These results suggest that HSCs with DNA repair defects such as MSH2-/- are PLSCs because they retain hematopoietic function, but also carry an obligate lymphomagenic potential within their T-cell progeny that is dependent on the thymic microenvironment.
Highlights
Mismatch repair (MMR) is an essential pathway for maintaining genomic integrity mainly by removing base mismatches and small insertion/deletion loops (IDLs) introduced during replication [1]
These results indicate that the cellular source of thymic lymphoma in MSH2-/- mice is in the bone marrow (BM)
The immunophenotypes of these lymphomas are similar in MSH2 -/- mice and in irradiated normal recipients transplanted with MSH2-/- BM cells
Summary
Mismatch repair (MMR) is an essential pathway for maintaining genomic integrity mainly by removing base mismatches and small insertion/deletion loops (IDLs) introduced during replication [1]. MMR gene defects have been most closely associated with hereditary nonpolyposis colorectal cancer (HNPCC) [2,3,4]. Deficiency in MMR is associated with subsequent mutation of critical downstream genes, resulting in deregulated cell proliferation and tissue-specific tumorigenesis [5,6]. Human HNPCC patients primarily develop cancers of the gastrointestinal tract, lymphomas and leukemias have been observed in certain kindreds [7,8].
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