Abstract 1910: Evolution of preleukemia stem cells to lymphoma initiating cells requires thymus in msh2-/- mice

Abstract

Abstract Thymic lymphomas have been thought to develop from disregulated differentiation and proliferation of developing thymocytes. T cell progenitors are generated from hematopoietic stem cells (HSCs) in the bone marrow (BM). Recent evidence strongly suggests that whereas transformation events may occur at different developmental stages, the initial mutation originates in the HSCs, and creates a preleukemic stem cell (PLSC). Subsequent mutations at either stem cell or progenitor cell levels would transform the PLSC into lymphoma/leukemia initiating cells (LIC). Maturation and proliferation of T cells depend on regulatory mechanisms in the thymus where the T-progenitors must interact with the microenvironment. Here we investigate the requirement of thymus environment for lymphoma development. Defects in the mismatch repair system (MMR) underlie hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome. Individuals with no MMR function present with childhood onset of hematological and brain malignancies. Mice carrying a null allele for the MMR gene, Msh2, are preferentially prone to develop thymic lymphomas and to a lesser extent, gastrointestinal tumors. Consistent with these findings in mice, MMR defects have also been observed in sporadic and hereditary hematological malignancies. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Using bone marrow transplantation, we found that limiting dilutions of MSH2-/- HSCs from young mice are able to reconstitute lethally irradiated wild-type recipients, and contribute to development of multiple hematopoietic lineages. However, all the recipients develop thymic lymphomas after a latency of 3-4 months post transplantation. Transplantation of different fractions of bone marrow cells or thymocytes from young MSH2-/- mice showed that only the HSC enriched fraction leads to lymphoma development. The lymphomas are transplantable, limiting dilution experiments showed that even 40 lymphoma cells could initiate T cell leukemia in sublethally irradiated secondary recipients within a month. In contrast, transplantation of the HSC enriched LSK fraction from the BM of lymphoma bearing mice into secondary recipients resulted in thymic lymphomas after a latency of 5 months. However, lymphoma development following transplant of HSC required an intact thymus and was not observed for more than 9 months if recipients were thymectomized, whereas this stromal requirement was not observed when transplanting T cell leukemicthymic lymphoma cells. These results suggested that MSH2-/- HSCs are PLSCs. While they retain full hematopoietic potential, their T-cell progeny gain lymphomagenic potential in the thymic microenvironment and become LICs. In this model, the evolution from PLSC to LIC is stromal-dependent. Citation Format: Yulan Qing, Stanton L. Gerson. Evolution of preleukemia stem cells to lymphoma initiating cells requires thymus in msh2-/- mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1910. doi:10.1158/1538-7445.AM2014-1910