Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation.
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.
Offman
Judith
J
Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, United Kingdom.
Opelz
Gerhard
G
Doehler
Bernd
B
Cummins
David
D
Halil
Ozay
O
Banner
Nicholas R
NR
Burke
Margaret M
MM
Sullivan
Dianne
D
Macpherson
Peter
P
Karran
Peter
P
D000208:Acute Disease; D001379:Azathioprine / Q000009:adverse effects; D020137:Base Pair Mismatch / Q000235:genetics*; D001853:Bone Marrow / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D005500:Follow-Up Studies; D016027:Heart Transplantation / Q000009:adverse effects* / Q000473:pathology; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000009:adverse effects; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000473:pathology; D007951:Leukemia, Myeloid / Q000453:epidemiology* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016040:Lung Transplantation / Q000009:adverse effects* / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000453:epidemiology* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors
D007166:Immunosuppressive Agents; D001379:Azathioprine