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Prepublished online as a Blood First Edition Paper on May 1, 2003; DOI 10.1182/blood-2002-10-3035.
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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1626-1633
HEMATOPOIESIS
Repopulating defect of mismatch repair–deficient hematopoietic stem cells
Jane S. Reese,
Lili Liu, and
Stanton L. Gerson
From the Division of Hematology/Oncology and Comprehensive Cancer Center,
Case Western Reserve University and University Hospitals of Cleveland,
Cleveland, OH.
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 transplantations of these
cells, alone or mixed with wild-type cells, into lethally irradiated healthy
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 with wild-type cells after each TMZ exposure. However, serial
repopulation by MSH2–/– cells was
deficient compared with wild-type cells. In recipients of mixed populations,
the MSH 2–/– 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
colony-forming unit (CFU) and
Sca+Kit+lin–-derived clones. Thus,
mismatch repair deficiency is associated with a hematopoietic repopulation
defect and stem cell exhaustion because of accumulation of genomic
instability.
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