Published August 4, 2017 | Blood

Researchers have hunted for years to find ways to disrupt the uncanny survival and self-renewal abilities of acute myeloid leukemia (AML) cells. 

So far, experts have found very few specific signaling pathways that lead to a weakness that can be therapeutically exploited.

One new approach may be to attack the polarity of AML cells, according to a study led by Benjamin Mizukawa, MD, James Mulloy, PhD, and Yi Zheng, PhD, and colleagues at Cincinnati Children’s.

The investigators determined that suppressing the gene CDC42 in leukemia-inducing cells (LICs) blocks progression of the disease in a mouse model. 

The gene expresses a protein, Cdc42, that plays a key role in controlling cell division. When that protein’s function is blocked, LICs lose cell polarity and division asymmetry, making it harder for them to multiply.

CDC42 expression is increased across a variety of AML subtypes, suggesting that this pathway is broadly upregulated. That could make CDC42 a useful target to alter leukemia-
initiating cell fate for differentiation therapy,” Mizukawa says.

Now, small molecules specifically targeting CDC42 activity are under preclinical development, Zheng says.

The compounds will require further in vivo pharmacokinetics, delivery, and toxicity testing before this promising approach can be ready for human clinical trials.

The experiments behind these findings required the involvement of several colleagues and shared facilities, including the Flow Cytometry Core, the Comprehensive Mouse and Cancer Core, and the Confocal Imaging Core.