Evolutionary Framework Frames Leukemia Mutations as Unavoidable Costs of Immune Defenses

In a conceptual review published in Frontiers in Cell and Developmental Biology, researcher Jiacheng Lou proposes the evolutionary cost theory of leukemogenesis, asserting that leukemia-driving mutations and oncogenic fusions represent recurring byproducts of indispensable immune and hematopoietic functions rather than random accidents. According to this framework, essential survival machinery—including enzymes enabling antigen receptor diversification, viral defense, stress-induced stem cell proliferation, and chromatin accessibility—inevitably inflicts collateral genomic damage. This enzymatic and replicative damage accumulates from fetal development onward, creating a universal reservoir of pre-leukemic variation across healthy individuals. Rather than viewing oncogenic alterations as stochastic errors, the author frames them as an unavoidable evolutionary price paid to maintain lifelong immunity and blood production. The framework emphasizes that progression from this benign reservoir into overt hematologic malignancy requires the convergence of four distinct conditions: continuous microenvironmental selection pressure, intrinsic defense breaches, failing immune restraint, and chronological time.

The proposed theory directly addresses prominent unresolved paradoxes within modern cancer biology, specifically explaining why leukemia-associated mutations occur so extensively in healthy populations without progressing to clinical disease. Prevailing paradigms, including Peter Nowell’s model of clonal evolution, Mel Greaves’ Darwinian selection framework, and Robert Schreiber’s cancer immunoediting hypothesis, explain how pre-existing mutant clones diversify, compete, and evade immune surveillance. However, the author argues that these models treat initial leukemogenic lesions as stochastic background events. Clinically, conditions such as clonal hematopoiesis of indeterminate potential, driven by recurring mutations in DNMT3A, TET2, and ASXL1, are present in 10 to 20 percent of adults older than 60 years, yet fewer than 1 percent convert to acute myeloid leukemia annually. Similarly, BCR-ABL1 fusions are detectable at low frequency in healthy adults, while ETV6-RUNX1 rearrangements arise prenatally at rates far exceeding the clinical incidence of childhood acute lymphoblastic leukemia.

To mechanistically account for this widespread reservoir of altered cells, the author catalogues a five-part inventory of normal physiological processes that inevitably generate structural variants and point mutations. The first source is V(D)J recombination, mediated by the RAG1 and RAG2 endonuclease complex, which cleaves DNA to generate lymphocyte receptor diversity but regularly acts on cryptic recognition sequences. The second source is somatic hypermutation executed by activation-induced cytidine deaminase, which deaminates cytosine to uracil during antibody maturation but creates off-target mutations at non-immunoglobulin loci. The third pathway involves the APOBEC3 cytidine deaminase family, which provides frontline antiviral defense while depositing collateral cytosine substitutions across human chromatin. The fourth process is the unavoidable replicative stress accompanying lifelong hematopoietic stem cell proliferation, where each stem cell division introduces approximately one new somatic mutation. Finally, the fifth component involves chromatin accessibility dynamics at lineage-specific genomic loci, where open conformations and topoisomerase activity render regulatory DNA fragile and vulnerable to translocations.

The mechanistic behavior of the RAG recombinase complex exemplifies how physiological functionality produces stereotyped leukemogenic damage rather than dispersed, random breakage. In fifty-seven analyzed diagnostic cases of ETV6-RUNX1 acute lymphoblastic leukemia, 76 percent of intrachromosomal rearrangements were deletions, with 39.5 percent displaying recognizable RAG motifs, and 70 percent exhibiting non-templated sequence insertions compared to only 6.7 to 19 percent in non-lymphoid malignancies. RAG-mediated deletions showed an approximately thirty-fold enrichment at active promoters and enhancers, mechanistically directed by the RAG2 plant homeodomain finger binding trimethylated histone H3 lysine 4 marks. Consequently, RAG activity recurrently disrupts key B-cell lineage regulators including CDKN2A, PAX5, BTG1, TBL1XR1, and ETV6, with roughly 49 percent of these deletion events striking established cancer genes. Because this enzymatic cutting is targeted toward actively transcribed regulatory regions required for lymphocyte maturation, the resulting structural alterations recur at predictable positions, illustrating why specific chimeric fusions and deletions form repeatedly in human cells.

Somatic hypermutation and cytidine deamination similarly demonstrate the dual nature of protective immunity functioning as a pervasive mutagenic engine. During normal immune responses, activation-induced cytidine deaminase deliberately targets immunoglobulin loci, yet its off-target enzymatic activity introduces mutations into known lymphoma and leukemia drivers, including BCL6, MYC, PIM1, RHOH, and PAX5. In parallel, the misincorporation and error-prone repair of these deaminated cytosines by DNA polymerase eta generates Signature 9, a distinct mutational footprint documented in chronic lymphocytic leukemia and mature B-cell lymphomas. Outside lymphoid-specific maturation, the APOBEC3 enzyme family operates as an essential innate barrier against viral pathogens, yet its off-target deamination of cytosine generates characteristic C-to-T and C-to-G substitutions, recognized internationally as mutational signatures SBS2 and SBS13. These APOBEC-driven signatures appear in more than half of all human cancer types, with hotspot lesions concentrated in transcriptionally active and accessible genomic regions, directly demonstrating that host antiviral defense systems persistently introduce mutations into normal hematopoietic progenitor genomes.

Beyond specialized enzymatic editing, the simple replicative demand required to maintain blood cell homeostasis contributes a steady, clock-like influx of genomic alterations. Landmark single-cell colony sequencing analyzing 3,579 hematopoietic colonies demonstrated that human hematopoietic stem and multipotent progenitor cells steadily accumulate approximately 17 somatic mutations per year while losing roughly 30 base pairs of telomeric length annually. In healthy individuals under the age of 65, hematopoiesis remains massively polyclonal, sustained evenly by 20,000 to 200,000 stem and progenitor cells. By contrast, in individuals older than 75 years, 30 to 60 percent of total blood production becomes dominated by just 12 to 18 distinct clones, many of which initiated expansion decades earlier before age 40 despite only 22 percent harboring identified classical driver mutations. Single-cell structural variant analyses reveal mosaic structural rearrangements in approximately one of every 43 hematopoietic progenitors throughout life, while large-scale population studies show that an average 70-year-old individual harbors up to 1.4 million protein-coding variants across their stem cell pool.

Because the accumulation of mutational costs is continuous and universal, the progression toward clinical leukemia depends heavily on environmental selection pressures that provide cost-bearing clones a competitive advantage. Chronic low-grade inflammation associated with aging, termed inflammaging, alters the bone marrow microenvironment by preferentially favoring clones that resist inflammatory exhaustion. Hematopoietic stem cells harboring mutations in DNMT3A or TET2 exhibit attenuated transcriptional responses to inflammatory signals, granting them a survival advantage over normal wild-type progenitors that undergo functional attrition during chronic stress. Experimental models demonstrate that elevated interleukin-1 signaling directly drives the expansion of TET2-deficient stem cells, an advantage abolished by genetic deletion of interleukin-1 receptor 1 or pharmacological treatment with anakinra. Beyond aging, external factors such as obesity and atherosclerosis exacerbate clonal expansion; in mouse models, atherosclerosis elevates stem cell proliferation by 1.5-fold, which modeling indicates produces a 3.5-fold increase in clonal hematopoiesis risk by age 70, establishing a feed-forward loop between vascular disease and clonal dominance.

Conversion from a pre-leukemic clone into acute leukemia additionally requires intrinsic defense breaches, extrinsic evasion, and an erosion of immune predator restraint integrated over time. Intrinsic resistance commonly involves disabling apoptotic checkpoints, such as TP53 mutations or the transcriptional upregulation of anti-apoptotic proteins like BCL-2, BCL-XL, and MCL-1. Extrinsically, pre-leukemic clones upregulate antiphagocytic signals, notably the CD47-SIRPα axis, which prevents marrow macrophages from clearing expanding progenitors, while suppressing human leukocyte antigens and CD155 to evade cytotoxic lymphocytes. Simultaneously, immune predator efficiency declines markedly across human lifespans through age-dependent thymic involution, which reduces naive T-cell output and contracts T-cell receptor diversity by roughly tenfold in adults over 65 years. The framework conceptualizes transformation across four chronological phases: silent mutation accumulation, selective clonal expansion, localized defense breaches, and exponential leukemic proliferation, explaining why most individuals harboring pre-leukemic alterations never experience the simultaneous collapse of all protective barriers.

The evolutionary cost theory offers logical explanations for several long-standing clinical paradoxes that conflict with classical multi-hit oncogenesis models. For example, infant acute lymphoblastic leukemia harboring MLL rearrangements displays an exceptionally low somatic mutation burden, averaging only 1.3 additional non-silent alterations per patient, contradicting the expectation that acute cancers require numerous cooperating hits. The framework explains that because MLL translocations arise in utero within actively proliferating fetal progenitors that possess developmentally immature apoptotic checkpoints and naive immune predation, a single genomic event is sufficient to trigger fulminant disease. Conversely, in inherited Fanconi anemia, genetic repair defects concentrate mutational costs by driving compensatory stem cell hyperproliferation, replicative stress, and heightened sensitivity to oxidative damage, accelerating leukemic risk hundreds of times over baseline without requiring unique biological mechanisms. In chronic myeloid leukemia, the BCR-ABL1 oncoprotein operates as a single comprehensive driver that simultaneously induces uncontrolled cellular proliferation, generates reactive oxygen species, suppresses normal DNA repair, and alters microenvironmental adhesion, single-handedly overcoming multiple physiological barriers over several years.

To distinguish itself from selection-only or purely stochastic paradigms, the cost framework outlines several falsifiable predictions, advocates a fundamental shift in clinical management, and clearly articulates its methodological boundaries. The author predicts that measuring specific mutational signatures, such as APOBEC and AID activity, will predict transformation risk from clonal hematopoiesis to acute leukemia independently of total mutation burden, and that individuals with lowest-decile T-cell receptor diversity will exhibit higher malignancy conversion rates. Therapeutically, because eradicating the foundational source of leukemogenic variation would require shutting down vital immune and hematopoietic functions, the clinical objective must shift from total clonal eradication toward ecological management, including microenvironmental anti-inflammatory therapies, menin inhibitors, and restoration of immune predation. The review notes important limitations: its synthesis is assembled narratively rather than systematically, quantitative cohort effects remain unpooled, and animal xenotransplant findings cannot be equated to native human clinical outcomes, framing the proposal as a refutable hypothesis.

Subject of Research: Evolutionary cost theory of leukemogenesis and mutational mechanisms in hematopoiesis

Article Title: Leukemia as the price of immunity? An evolutionary cost framework

Article References: Lou, J. (2026). Leukemia as the price of immunity? An evolutionary cost framework. Frontiers in Cell and Developmental Biology, 14, Article 1947508. https://doi.org/10.3389/fcell.2026.1947508

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1947508

Keywords: clonal hematopoiesis, evolutionary cost theory, leukemogenesis, mutational signatures, V(D)J recombination, somatic hypermutation, RAG endonuclease, activation-induced cytidine deaminase, APOBEC deaminases, hematopoietic stem cells, immune surveillance, thymic involution, bone marrow microenvironment, acute lymphoblastic leukemia, acute myeloid leukemia, tumor suppressor genes, clonal evolution