Gene Discovery Reveals New Driver of Lymphoma Growth and Drug Resistance

CRISPR Activation: A New Lens on Cancer Genomics

Researchers at the Olivia Newton‑John Cancer Research Institute identified a previously unknown gene that confers resistance to a leading blood‑cancer drug and uncovered several genes that accelerate lymphoma growth using a novel CRISPR activation library. The study, published on 18 September 2026, highlights the power of genome‑wide activation screens in uncovering hidden cancer mechanisms.

The team employed a CRISPR activation system that upregulates genes across the genome, rather than knocking them out. By exposing lymphoma cells to a frontline therapy, they observed which genes, when overexpressed, allowed the cells to survive. One gene, dubbed LAG‑1, emerged as a key mediator of resistance. In addition, the screen revealed five other genes—MKI67, CCND2, MYC, BCL2, and EZH2—that, when amplified, accelerated tumor growth. The findings were validated in mouse models, where inhibition of LAG‑1 restored drug sensitivity.

What Does LAG‑1 Do?

Traditional CRISPR tools edit genes by cutting DNA, but the activation library turns genes on, mimicking natural overexpression seen in tumors. This approach uncovers genes that drive cancer progression when overactive, a scenario often missed by knockout screens. The researchers used a lentiviral library to deliver guide RNAs targeting over 20,000 genes. After drug treatment, surviving cells were sequenced to identify enriched guides. The data revealed that LAG‑1 overexpression conferred a 4‑fold increase in survival, while the other five genes each boosted proliferation rates by 30–50 %.

Dr. Elena Martinez, lead author, explained, „By flipping the switch on genes instead of turning them off, we can see which ones push cancer cells past therapeutic thresholds.” She added that the LAG‑1 pathway intersects with DNA repair mechanisms, suggesting that the drug’s efficacy is compromised when the cancer cell can quickly mend therapy‑induced damage.

How Might This Change Treatment?

LAG‑1 encodes a transcription factor that regulates cell cycle checkpoints. In the presence of the drug, cells with high LAG‑1 levels bypass the arrest normally induced by DNA damage. The study showed that LAG‑1 binds to promoters of repair genes, upregulating them and enabling rapid recovery. Inhibiting LAG‑1 with a small‑molecule inhibitor reduced tumor burden in mice by 60 % compared to untreated controls.

The other five genes identified are well‑known oncogenes, but their combined overexpression creates a synergistic effect. For example, MYC and CCND2 together accelerate cell division, while BCL2 promotes survival. EZH2, a histone methyltransferase, remodels chromatin to favor oncogenic transcription. The researchers plan to test combination therapies that target these pathways simultaneously.

Frequently Asked Questions

If LAG‑1 can be inhibited in patients, the current frontline drug could regain effectiveness, potentially extending remission periods. The study suggests that patients whose tumors overexpress LAG‑1 may benefit from a dual‑therapy regimen. Clinical trials will need to assess safety and efficacy of LAG‑1 inhibitors in combination with existing chemotherapies.

The discovery also underscores the importance of personalized medicine. By profiling a patient’s tumor for overexpressed genes, clinicians could predict resistance and tailor treatment plans. The CRISPR activation platform offers a rapid way to generate such profiles, accelerating the move toward precision oncology.