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Blood, 1 August 2004, Vol. 104, No. 3, pp. 822-828.
Prepublished online as a Blood First Edition Paper on April 15, 2004; DOI 10.1182/blood-2003-11-3938.
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NEOPLASIA
Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation
Judith Offman,
Gerhard Opelz,
Bernd Doehler,
David Cummins,
Ozay Halil,
Nicholas R. Banner,
Margaret M. Burke,
Dianne Sullivan,
Peter Macpherson, and
Peter Karran
From the Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, United Kingdom; Harefield Hospital, Harefield, United Kingdom; and Institut für Immunologie, Abteilung Transplantations-immunologie, Heidelberg, Germany.
Immunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplant-related AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selective proliferation of MMR-defective, azathioprine-resistant myeloid cells may contribute significantly to the development of AML/MDS in patients who have received organ transplants. Identifying azathioprine as a risk factor for AML/MDS suggests that discontinuing the use of azathioprine as an immunosuppressant might reduce the incidence of posttransplantation AML/MDS.
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