Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Hematopoietic malignancies arise from mutations in hematopoietic stem cells (HSCs).
• Preleukemic stem cells (PLSCs) can develop into lymphoma/leukemia initiating cells (LICs) through further mutations.
• Thymic lymphomas are thought to originate from developing thymocytes, with T-cell development and lymphomagenesis influenced by the thymus microenvironment.

Purpose of the Study:

• To investigate the existence and evolution of PLSCs into LICs using MSH2-/- mice as a model.
• To determine the role of HSCs with DNA repair defects in thymic lymphoma development.

Main Methods:

• Bone marrow (BM) transplantation from young MSH2-/- mice into lethally irradiated wild-type recipients.
• Transplantation of different BM cell fractions and thymocytes from MSH2-/- mice.
• Analysis of recipients for hematopoietic reconstitution and lymphoma development.
• Assessment of lymphoma incidence in thymectomized recipients.

Main Results:

• MSH2-/- BM cells fully reconstituted hematopoiesis in recipients but led to thymic lymphomas within 3-4 months.
• HSC-enriched fractions from MSH2-/- mice reconstituted hematopoiesis and subsequently developed lymphomas.
• Lymphoma development was abrogated in thymectomized recipients, indicating dependence on the thymic microenvironment.

Conclusions:

• Hematopoietic stem cells with DNA repair defects (e.g., MSH2-/-) function as PLSCs.
• These PLSCs possess lymphomagenic potential in their T-cell progeny, contingent upon the thymic microenvironment.
• The thymus microenvironment plays a critical role in the progression from PLSC to LIC in thymic lymphomas.