Figure 2.

Schematic representations of somatic reversion in the hematopoietic system that eventually results in distinct hematological and immunological reconstitution. (A) A somatic reversion event can occur at a late stage of the hematopoietic hierarchy and provide a selective advantage to a restricted lineage. The diagram shows the occurrence of reversion in a T/NK-cell progenitor. When T-cell lineage selectively exhibits a proliferative advantage, somatic mosaicism will be detected only in the T-cell population. This model is applicable to the reversion mosaicism in the context of severe combined immunodeficiency or a T-cell deficiency. (B) A somatic reversion event can occur in less-differentiated hematopoietic progenitor cells. For example, when reversion mutation occurs in a multipotent progenitor (MPP), cells from all hematopoietic lineages can theoretically harbor the same reversion mutation. However, when the T-cell lineage selectively represents a proliferative advantage, somatic mosaicism will seemingly be detected only in the T-cell lineage. This selective advantage may depend on intrinsic gene function for T-cell proliferation and/or persistent antigen-specific responses. In disorders with T-cell lymphopenia such as severe combined immunodeficiency, homeostatic expansion will further provide a positive effect on proliferative advantage over the T-cell lineage. (C) When the germline mutation is deleterious for all hematopoietic lineages (i.e., the function of the affected gene is equally essential for all hematopoietic lineages), the reversion mutation in less-differentiated progenitor cells can reconstitute the whole hematopoietic system. In this scenario, somatic mosaicism can be detected in all compartments. Bone marrow failure disorders may be applicable to this model. HSC, hematopoietic stem cell; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; GMP, granulocyte-monocyte progenitor; MEP, megakaryocyte-erythroid progenitor; NK, natural killer.