Yale Study Identifies a New Class of Drug Targets for Aggressive Leukemia

Hyperactive signaling pathways of some aggressive blood cancer cells can be tamped down by a previously unrecognized protein complex, ensuring the cancer’s survival. If one component of the complex is deleted or removed, the cancer cells are sent into overdrive and die, finds a Yale-led study published as the cover story Feb. 10 in Science Signaling.

The surface receptor CD25 is one of these components, typically a marker of activated immune cells, but also associated with aggressive cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

“Detecting CD25 in a patient sample has been known for many years as a sign of poor clinical outcomes,” says senior author Markus Müschen, MD, PhD, director of Yale School of Medicine’s Center of Molecular and Cellular Oncology (CMCO).

For this reason, the Yale researchers set out to understand the link between CD25’s presence in a subset of B-cell ALL, the most common type of ALL, and AML patients with poor response to otherwise effective therapies. They examined clinical data from leukemia patients, and implemented genetic modeling that allowed researchers to chart, via mass spectrometry, CD25’s interactions with other proteins within the cancer cells in a living organism and to test therapies.

Most cancers thrive and depend on strong activation signals, which are exploited by therapeutic drugs designed to suppress cancer cell activation. In contrast, the study found that leukemia cells express CD25 on the cell surface to assemble a protein complex that dampens activity and makes cancer cells grow at a slower, steadier pace.

“We were surprised that leukemia cells grow in a Goldilocks zone and depend on a ‘molecular brake’ to slow down, so their activation levels are just right,” says Müschen, who also is Arthur H. and Isabel Bunker Professor of Hematology and chief of the Basic Science Division at Yale Cancer Center.

In addition to revealing the previously unrecognized role for CD25 in acute leukemia subpopulations with poor prognosis, the study also highlighted the dependency of tyrosine kinase-driven leukemias on feedback control for their survival.

While drug discovery efforts for aggressive cancers are almost entirely focused on inhibitors to suppress activation signals, the Yale-led study sheds light on an unexplored class of new cancer drugs that are being designed to hyperactivate leukemia cell signaling. These drugs that target CD25 and associated proteins can push leukemia cells beyond a maximum threshold of activation that they can tolerate.

Müschen and his team at Yale co-led an international consortium of scientists pursuing the counterintuitive idea to hyperactivate signaling, causing cancer cells to burn out, rather than inhibiting activation signals in cancer.

In addition to a half dozen researchers in the CMCO and the Yale Department of Immunobiology, the study included collaboration with scientists at Korea University in Seoul, City of Hope Comprehensive Cancer Center, Loma Linda University, University of California San Francisco, University of Pennsylvania, Mayo Clinic, and Montefiore Medical Center.