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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.
 Previous Article | Next Article 
Submitted November 17, 2003
Accepted March 30, 2004
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*
Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms, United Kingdom
Abteilung Transplantations-immunologie, Institut fur Immunologie, Heidelberg, Germany
Harefield Hospital, Harefield, United Kingdom
* Corresponding author; email: peter.karran{at}cancer.org.uk.
Immunosuppression following organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in transplant patients and whether this might be related to a particular immunosuppressive treatment. Data from more than 170000 patients indicated that organ transplantation is associated with a significantly increased risk of acute myeloid leukemia (AML). AML was more frequent following heart and/or lung transplant than kidney transplant 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 patients bone marrow, seven of seven transplant-related AML/myelodysplastic syndrome (MDS) cases exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Since 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 organ transplant patients. The identification of azathioprine as a risk factor for AML/MDS suggests that the incidence of post-transplant AML/MDS might be reduced by discontinuing its use as an immunosuppressant.
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