In a small research lab in Memphis, scientists have found a promising new way to attack one of childhood leukemia's toughest targets—and they did it by going after a different protein entirely.
Most children with leukemia today survive. But a small group with a specific genetic feature called KMT2A rearrangements still face a harder road. Their cancers are driven by powerful proteins like MYC and HOXA9 that have been nearly impossible to target with existing drugs. MYC in particular has earned the label "undruggable"—its structure and role in the body make it a notoriously difficult target.
Now, researchers at St. Jude Children's Research Hospital have discovered that blocking a protein called RBM5 can effectively cut the brakes on MYC, destabilizing it and causing cancer cells to die. In mouse models of this aggressive leukemia, removing RBM5 more than doubled survival time. Crucially, removing RBM5 from normal blood-forming stem cells caused no damage at all—a sign that future treatments targeting this pathway might be both effective and safe.
"When we removed RBM5 from leukemic stem cells, we doubled survival in our mouse models, but when we removed it from normal blood-forming stem cells, we saw no effect on hematopoiesis," said Dr. Chunliang Li, a co-corresponding author of the study. "That makes it a promising candidate for developing more precise, less toxic therapies."
The team, led by first author Mengli Zhang, found that RBM5 physically interacts with MYC inside cancer cells. Without RBM5 present, MYC can no longer hold onto the DNA regions that activate its own growth signals. The cancer's self-reinforcing loop breaks down, and the leukemia cells eventually die.
The findings, published in the journal Leukemia, suggest a new strategy: instead of trying to hit MYC directly—which scientists have struggled to do for decades—researchers could aim at RBM5 instead, disrupting the partnership that keeps MYC active.
"If we can find a way to disrupt the physical interaction between these two proteins, we may have found a way to destabilize MYC in leukemia cells," Li said. "That gives us a new therapeutic direction for these difficult-to-treat subtypes."
The research is still early. The team plans to continue studying how RBM5 and MYC work together, with the goal of eventually developing drugs that could be tested in clinical trials. But for children and families facing these harder-to-treat leukemias, the discovery offers a meaningful new avenue of hope.