For more than two decades, researchers have tried to explain why AID targets a small set of genes while leaving thousands of other active genes untouched.

How do MLLT1 and MLLT3 aim the enzyme?

Di Noia's team discovered that the two proteins recognize specific chemical marks on histones — the spool-like proteins around which DNA is wrapped. Genome regions with exceptionally high concentrations of MLLT1 and MLLT3 correspond precisely to the sites where AID induces mutations. The researchers observed this pattern in animal models and in humans, including lymphoma cells.

The decisive experiment came when the scientists removed both proteins at once. Antibody diversification and AID-induced mutations virtually disappeared — even though AID still stuck to DNA and the affected genes kept being read.

The study shows that MLLT1 and MLLT3 interact directly with AID and concentrate it near targeted genes. The proteins appear to form tiny molecular compartments called "condensates," which act as gathering points for the enzyme. Because AID on its own is naturally inefficient, packing it into these local hubs greatly raises the odds that a mutation will occur.

"Our findings reveal a previously unknown layer of control," said Di Noia. "Only regions of the genome that accumulate sufficient levels of MLLT1 and MLLT3 can concentrate AID enough to enable efficient mutation. This helps explain how evolution has been able to tolerate such a dangerous enzyme without broadly compromising genome integrity."

What could this mean for blood cancers?

The discovery offers a conceptual framework for understanding why certain genome regions are frequently mutated in lymphomas and other cancers derived from B cells. It also hints at a therapeutic angle: molecules that inhibit MLLT1 and MLLT3 reduced both AID-dependent mutations and chromosomal translocations — a kind of DNA scrambling linked to cancerous transformation — in experimental models.

These results remain preliminary, and the inhibition experiments so far come from laboratory models rather than patients. Still, the proteins could become future therapeutic targets for slowing certain lymphomas or limiting treatment resistance. Because MLLT1 inhibitors are already in clinical development for certain forms of leukemia, repurposing them might eventually be considered for diseases in which AID drives tumor progression.

Publication details

Noé Seija et al., "Histone readers MLLT1 and MLLT3 concentrate AID to confer locus specificity," Nature (2026). DOI: 10.1038/s41586-026-11087-1.