Leukemia as the price of immunity? An evolutionary cost framework

Current evolutionary frameworks explain how leukemic clones are selected, diversify, and escape immune surveillance, yet they do not explain why leukemia-associated variants are so abundant in healthy individuals. We propose the evolutionary cost theory of leukemogenesis: driver mutations and oncogenic fusions are not random accidents but, in large part, recurring byproducts (“costs”) of hematopoietic functions essential for survival. The same molecular machinery that enables V(D)J recombination, somatic hypermutation, APOBEC-mediated antiviral defense, stress-responsive hematopoietic stem cell (HSC) proliferation, and multilineage chromatin accessibility necessarily generates collateral genomic damage. These costs accumulate from development onward, creating a universal variant reservoir upon which selection, clonal evolution, and immunoediting subsequently act. Conversion from cost to clinical disease requires the convergence of four conditions: selection pressure, defense breach, failure of immune restraint—waning predation in aging, immature predation in early life—and time. This framework resolves several paradoxes, including the low mutation burden of infant MLL-rearranged acute lymphoblastic leukemia (ALL), the accelerated risk in Fanconi anemia, and the single-driver sufficiency of chronic myeloid leukemia, and generates falsifiable predictions that distinguish it from multi-hit and selection-only models. Therapeutically, the goal shifts from eradication, which would require eliminating immunity itself, to ecological management: fortifying defenses, modifying the marrow microenvironment, breaking positive feedback loops, restoring immune predators, and establishing prevention windows in high-risk clonal hematopoiesis.