Hierarchical tissue structure creates history-dependent barriers to clonal invasion

Hierarchical tissue structures in higher organisms are governed by stem and progenitor cell compartments that are regulated by feedback mechanisms. Somatic mutations create genetically distinct clones, with their evolutionary success relying not only on their fitness but also on the tissue architecture they arise in. Previous research demonstrated that this hierarchical organization establishes invasion barriers, hindering the expansion of advantageous mutants from downstream compartments unless their fitness surpasses a critical level.

In this study, the framework is expanded to account for populations with multiple competing mutant clones. A general invasion criterion is derived, revealing that the threshold for mutant expansion is influenced by the equilibrium established by resident clones, implying that the evolutionary history of the system plays a crucial role.

The presence of established clones alters the invasion barriers encountered by subsequent mutants, rendering clonal evolution history-dependent. The theory predicts competitive exclusion between clones inhabiting the same compartment, and it is shown that resident clones can hinder the establishment of later mutants.

The predictions of the theory were tested using a model previously parameterized for murine hematopoiesis. The results provide a mechanistic explanation for the observed mutation-order effects involving JAK2 V617F and TET2 mutations in myeloproliferative neoplasms. The findings highlight invasion barriers as a fundamental principle governing history-dependent clonal evolution in hierarchical tissues.