Genetics of donor cell leukemia in acute myelogenous leukemia and myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapeutic modality for patients with acute myelogenous leukemia (AML) with poor risk features. Nonetheless, roughly 30% of such patients have leukemia recurrence and up to 2% of these are donor-derived leukemias, in which malignancy develops in the donor's transplanted cells, despite extremely low rates of leukemia in the donors themselves. Notably, over 20% of these malignancies carry chromosome 7 abnormalities nearly all of which are monosomies. Recent advances in whole exome and genome sequencing have allowed for detection of candidate genes that likely contribute to the development of AML in donor cells (donor leukemia, DCL). These genes include CEBPA, GATA2, JAK2, RUNX1, DDX41, EZH2, IDH1/2, DNMT3A, ASXL1, XPD, XRCC3, and CHEK1. The potential roles of variants in these genes are evaluated based on familial clustering of MDS/AML and corresponding animal studies demonstrating their leukemogenic nature. This review describes the spectrum of genetic aberrations detected in DCL cases in the literature with regard to the character of the individual cases, existing family cohorts that carry individual genes, and functional studies that support etiologic roles in AML development. DCL presents a unique opportunity to examine genetic variants in the donors and recipients with regards to progression to malignancy.