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Prepublished online as a Blood First Edition Paper on May 1, 2003; DOI 10.1182/blood-2002-10-3035.
Submitted October 4, 2002
Accepted April 18, 2003
Repopulating defect of mismatch repair-deficient hematopoietic stem cells
Jane S Reese, Lili Liu, and Stanton L Gerson*
Division of Hematology Oncology, Case Western Reserve University, Cleveland, OH, USA
* Corresponding author; email: slg5{at}po.cwru.edu.
Mismatch repair deficiency is associated with carcinogenesis, increased spontaneous and induced mutagenesis and resistance to methylating agents. In humans, leukemias and lymphomas arise in the background of mismatch repair deficiency, raising the possibility that hematopoiesis is abnormal as well. To address hematopoiesis in MSH2 -/- mice, we collected marrow and performed serial transplantation of these cells, alone or mixed with wild type cells, into lethally irradiated normal mice. Transplant recipients were observed or treated with the methylating agent, temozolomide (TMZ). Methylating agent tolerance was evident by the competitive survival advantage of MSH2-/- marrow progenitors compared to wild type cells after each TMZ exposure. However, serial repopulation by MSH2 -/- cells was deficient compared to wild type cells. In recipients of mixed populations, the MSH2-/- cells were lost from the marrow and mice receiving MSH2-/- cells plus TMZ could not be reconstituted in the third passage whereas all wild type cell recipients survived. No differences in telomere length, cell cycle distribution or homing were observed, but an increase in microsatellite instability was seen in the MSH2-/- early progenitor CFU and Sca+Kit+lin- derived clones. Thus, mismatch repair deficiency is associated with a hematopoietic repopulation defect and stem cell exhaustion due to accumulation of genomic instability.
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