First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation

Donor cell leukemia after allogeneic hematopoietic stem cell transplantation might provide a unique human model for our understanding of leukemogenesis in vivo. We hypothesized that the 2-genetic-hits model may contribute to the leukemization of donor cells and first evaluated these genetic mutations that are implicated in the development of acute myeloid leukemia in a donor cell leukemia patient and donor. The patient and his donor-sister both harbored a germline mutation in CEBPA (584_589dup). Susceptible donor hematopoietic cells evolved to overt acute myeloid leukemia by developing 2 somatic CEBPA mutations (247dupC and 914_916dup) in the patient's microenvironment. These were identical to the acquired mutations identified in leukemic cells that originated from the patient during de novo acute myeloid leukemia. Our results provide the first report of multiple mutations of CEBPA contributing to the transformation of donor cells to the leukemic phenotype and provide clues to support the multiple-genetic-hits mechanism of donor cell leukemia. (Blood. 2011; 117(19):5257-5260)