Ionizing radiation and hematopoietic malignancies: altering the adaptive landscape

Abstract

Somatic evolution, which underlies tumor progression, is driven by two essential components: (1) diversification of phenotypes through heritable mutations and epigenetic changes and (2) selection for mutant clones which possess higher fitness. Exposure to ionizing radiation (IR ) is highly associated with increased risk of carcinogenesis. This link is traditionally attributed to causation of oncogenic mutations through the mutagenic effects of irradiation. On the other hand, potential effects of irradiation on altering fitness and increasing selection for mutant clones are frequently ignored. Recent studies bring the effects of irradiation on fitness and selection into focus, demonstrating that IR exposure results in stable reductions in the fitness of hematopoietic stem and progenitor cell populations. These reductions of fitness are associated with alteration of the adaptive landscape, increasing the selective advantages conferred by certain oncogenic mutations. Therefore, the link between irradiation and carcinogenesis might be more complex than traditionally appreciated: while mutagenic effects of irradiation should increase the probability of occurrence of oncogenic mutations, IR can also work as a tumor promoter, increasing the selective expansion of clones bearing mutations which become advantageous in the irradiation-altered environment, such as activated mutations in Notch1 or disrupting mutations in p53.

Figure 1

Prevailing paradigm and adaptive oncogenesis models of cancer development. (A) Conventional Model: IR exposure increases the production of oncogenic mutations and the accumulation of these mutations leads to cancer development. (B) Adaptive Oncogenesis: The promotion of cancer development by IR exposure acts through decreasing progenitor cell fitness and altering the microenvironment, which increase selection for adaptive oncogenic mutations, promoting the initiation of cancer.

Figure 2

IR-induced alteration of the stromal compartment can influence selection for mutant progenitor cells. The cell marked with an X depicts a mutant progenitor cell; arrows depict positive influences on progenitor cells; bars represent inhibitory influences on progenitor cells; the weight of the arrow or bar represents the predicted magnitude of influence the stromal cell exerts on the progenitor cell.

Figure 3

Adaptive landscape of stem cell populations under normal conditions and in irradiated or aging environments. The x- and y-axes represent the potential genetic and epigenetic diversity. Adjacent points on the X-Y landscape correspond to more similar (epi)genotypes. The z-axis (vertical axis with peaks above the plane) represents fitness.