The Goldilocks Zone: New Study Clarifies CD25’s Role in High-Risk AML, ALL

CD25 expression has long been recognized as an adverse prognostic marker in acute leukemias including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). A new study from the Yale School of Medicine provides important mechanistic insight into why CD25-positive disease tends to have more aggressive clinical courses.¹

The work, published in Science Signaling, used genetic mouse models and gene-editing techniques to interrogate CD25 function in tyrosine kinase–driven AML and ALL. In an interview with Targeted Oncology, Markus Müschen, MD, PhD, Yale School of Medicine and study senior author, explained that CD25 is more than just a surface marker that flags high-risk disease—it plays an active role in how leukemia cells regulate growth signals.

The study builds upon earlier clinical observations from an ECOG study in which a small CD25-positive subpopulation in AML was associated with significantly worse outcomes, independent of established biomarkers.² Similar observations have been reported in ALL, positioning CD25 as an “ominous” diagnostic feature in clinical practice, describes Müschen.

Müschen described the study’s findings as unexpected, embracing a “Goldilocks” principle of leukemia biology: leukemia cells need growth signaling that is not too weak and not too strong, but “just right.” While oncogenic tyrosine kinase signaling drives proliferation, too much signaling can stress or damage the leukemia cell. CD25 appears to help fine-tune this signaling intensity, keeping it in an optimal range that allows leukemia cells to grow while remaining resilient under treatment pressure. This may help explain why CD25-positive leukemias are often more treatment-resistant and associated with poorer outcomes.

“Recent observations in other cancer types, including colorectal cancer, prostate cancer, Ewing sarcoma, already supported this emerging idea of a ‘Goldilocks’ zone of an optimal sweet spot of signaling strength,” Müschen said. “I think in our case, we contributed another aspect of how this works in cancer—but in this case, from the perspective of tyrosine kinase–driven AML and ALL, and we think that's exciting, because it not only explains why CD25 is a therapeutic target, but also nominates additional molecules that are part of this inhibitory complex as future drug targets.”

REFERENCES

1. Lee J, Sun R, Kume K, et al. Dynamic feedback control of oncogenic tyrosine kinase signaling in acute leukemia. Sci Signal. 2026;19(924). doi:10.1126/scisignal.adw5054

2. Gönen M, Sun Z, Figueroa ME, et al. CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900. Blood. 2012;120(11):2297-2306. doi:10.1182/blood-2012-02-414425