Autophagy Variants Linked With Increased Risk of CLL

A large international study has identified 4 genetic variants associated with an increased risk of chronic lymphocytic leukemia (CLL). The findings, published in Blood Advances, provide new insights into disease biology and may eventually help refine risk assessment in individuals predisposed to this common blood cancer.¹

While the work does not immediately alter patient management, it could inform future genetic screening efforts, particularly for individuals with a family history of hematologic cancers. It may also guide research into novel therapeutic strategies that exploit immune vulnerabilities uncovered by these variants.

The variants are tied to autophagy, a cellular process involved in recycling damaged or unnecessary components,² which has been linked to both the risk and prognosis of CLL.

“Recent studies implicate autophagy, a conserved catabolic process promoting cell survival, in CLL risk and prognosis. Autophagy contributes to malignant transformation, chemotherapeutic response, and has been observed in both hematologic malignancies and solid tumors,” explained the researchers, adding, “Several reports show that autophagy has a pro-survival role, and its inhibition induces programmed cell death in CLL.”

Researchers examined more than 55,000 single nucleotide polymorphisms (SNPs) in 234 autophagy-related genes across 4 major European cohorts. The analysis included 5472 patients with CLL and over 726,000 healthy controls. After statistical filtering and replication in an independent cohort, the team confirmed strong associations between specific variants in the CDKN2A and BCL2 genes and CLL risk.

The most significant finding involved the CDKN2A_rs3731204 variant, each copy of which reduced the likelihood of developing CLL by 22%. CDKN2A encodes p16, a key cell-cycle inhibitor that prevents unchecked cell proliferation. Higher expression of this gene, linked to the protective allele, appears to guard against malignant transformation.

Variants within the BCL2 gene were also independently tied to CLL risk. Unlike many oncogenes that drive proliferation, BCL2 promotes survival by blocking apoptosis, or programmed cell death. Overexpression of BCL2 has long been recognized in CLL, but the mechanisms driving this overactivity have remained uncertain.

The newly identified BCL2 variants—rs1026825, rs12457371, and rs4940571—seem to influence immune cell populations and cytokine signaling, detailed the researchers. For example, carriers of the rs4940571 risk allele showed increased regulatory T cell counts and reduced levels of interferon-gamma, a cytokine critical for anti-tumor immunity.

The study also validated previously reported associations in FAS, BCL2, and BAK1 genes, strengthening the evidence that apoptotic and autophagy-related pathways are central to CLL biology. In particular, the FAS_rs1926194 variant was linked to elevated levels of TRAIL and CD40, molecules involved in immune signaling and tumor interactions.

Although the researchers initially hypothesized that the variants might directly alter the rate at which cells recycle their contents, known as autophagy flux, laboratory assays did not support this. Instead, the genetic changes appeared to exert their influence through modulation of immune responses and T-cell subsets. For instance, individuals carrying protective CDKN2A alleles had lower numbers of naïve and double-positive T cells, both of which have been implicated in CLL progression.

“This confirms that these genes might not influence disease onset through the control of this mechanism, but rather through the modulation of multiple immunological and non-immunological mechanisms, implicating specific immune cells, cytokines, and multiple transcription factors,” explained the researchers.

One key question identified by the findings was whether these genetic variants affect disease course once CLL develops. The analysis found no significant associations with either overall survival (OS) or time to first treatment (TTFT), suggesting that the variants play a role in initiating CLL but not in prognosis, such as how aggressive the disease becomes or how patients respond to therapy.

The researchers noted that their findings need to be validated in more diverse patient populations, as their study focused on individuals of European ancestry. Additionally, although functional assays provided suggestive links between the variants and immune activity, many associations lost significance after correcting for multiple testing, highlighting the complexity of untangling genetic effects in cancer biology.

References:

1. Cabrera-Serrano AJ, Sánchez-Maldonado J, Rodríguez-Sevilla JJ, et al. Identification of four autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia. Blood Adv. Published online September 5, 2025. doi:10.1182/bloodadvances.2025017345

2. Gómez-Virgilio L, Silva-Lucero MC, Flores-Morelos D-S, et al. Autophagy: a key regulator of homeostasis and disease: an overview of molecular mechanisms and modulators. Cells. 2022;11(15):2262. doi:10.3390/cells11152262