A PTBP1-CDC42 splicing axis regulates leukemia growth and venetoclax sensitivity in acute myeloid leukemia

Acute myeloid leukemia (AML) is a deadly form of blood cancer with high relapse rates and poor outcomes, particularly in elderly or unfit patients who cannot handle intensive chemotherapy. Venetoclax, a BCL2 inhibitor, has shown promise in improving initial responses in high-risk AML patients, but relapses are almost always inevitable, emphasizing the need for new treatment options.

Researchers have now discovered that the RNA-binding protein PTBP1 plays a crucial role in AML, and its depletion hampers leukemic growth both in laboratory tests and animal models. This reduction in growth is linked to widespread changes in splicing and a global slowdown in protein synthesis.

Through a comprehensive analysis of gene expression and RNA binding, scientists found that PTBP1 controls a splicing program related to Rho GTPase signaling, with CDC42 being a crucial downstream target. When PTBP1 is lost, there is a shift in splicing from CDC42-v1 to CDC42-v2, resulting in diminished GTPase activity and inhibited protein synthesis.

Pharmacological blockade of CDC42 specifically triggers cell death in AML cells without harming healthy blood-forming cells. Furthermore, inhibiting CDC42 significantly boosts the effectiveness of venetoclax in treating AML.

These findings highlight PTBP1 as a vital regulator of AML cell survival and uncover a potential therapeutic combination that takes advantage of AML's reliance on the PTBP1-CDC42 signaling pathway to improve the performance of venetoclax-based treatments.