Clonal evolution in inherited marrow failure syndromes predicts disease progression

Progression to myelodysplastic syndromes (MDS) and acute myeloid leukemia is one of the most serious complications of the inherited bone marrow failure and MDS-predisposition syndromes. Given the lack of predictive markers, this risk can also be a source of great uncertainty and anxiety to patients and their providers alike. Recent data show that some acquired mutations may provide a window into this risk. While maladaptive mechanisms, such as monosomy 7, are associated with a high risk of leukemogenesis, mutations that offset the inherited defect (known as somatic genetic rescue) may attenuate this risk. Somatic mutations that are shared with age-acquired clonal hematopoiesis mutations also show syndrome-specific patterns that may provide additional data as to disease risk. This review focuses on recent progress in this area with an emphasis on the biological underpinnings and interpretation of these patterns for patient care decisions.