Revertant somatic mosaicism as a cause of cancer

Abstract

Revertant (somatic) mosaicism is a spontaneous correction of a causative mutation in patients with congenital diseases. A relatively frequent event, revertant mosaicism may bring favorable outcomes that ameliorate disorders, and is therefore called “natural gene therapy.” However, it has been revealed recently that “overcorrection” of inherited bone marrow failure in patients with sterile alpha motif domain containing 9 (SAMD9)/9L syndromes by revertant mosaicism induces myelodysplastic syndrome (MDS) with monosomy 7 that occasionally proceeds to acute myelogenous leukemia (AML). In this review, we interpret very complex mechanisms underlying MDS/AML in patients with SAMD9/9L syndromes. This includes multiple myeloid tumor suppressors on the long arm of chromosome 7, all of which act in a haploinsufficient fashion, and a difference in sensitivity to interferon between cells carrying a mutation and revertants. Overcorrection of mutants by somatic mosaicism is likely a novel mechanism in carcinogenesis.

Abstract

A scheme of myelodysplastic syndrome (MDS) carrying ‐7/del(7q). In patients with SAMD9/9L syndromes, bone marrow cells with SAMD9/9L ^+/− (revertants) show a high sensitivity to growth factors and a low sensitivity to (the suppressive effects of) interferon (IFN). In addition, surrounding bone marrow cells (SAMD9/9L ^+/mut) have a high sensitivity to IFN. As a result, the rapid expansion of a ‐7/del(7q) clone causes an “overcorrection,” leading to MDS. This mechanism would be partially applied to sporadic MDS patients with ‐7/del(7q) in old age.