Abstract
<title>Abstract</title> <p>B-cell acute lymphoblastic leukemia (B-ALL) remains the most common pediatric cancer, and relapse continues to be a major cause of treatment failure. Although the bone marrow microenvironment is known to promote leukemic persistence and dissemination, the mechanisms mediating these effects remain poorly defined. Here, we identify activin A as a microenvironment-derived driver of B-ALL progression and relapse. Activin A and its receptors were significantly overexpressed in pediatric and adolescent B-ALL at diagnosis and relapse. Functionally, activin A enhanced leukemic cell migration, adhesion, transendothelial migration, and bone marrow organoid colonization by promoting actin polymerization. We previously demonstrated that the actin-binding protein cortactin is a key regulator of B-ALL dissemination and relapse. Consistent with this role, pharmacological inhibition of activin A signaling suppressed transendothelial migration and organoid colonization in leukemic cells expressing high levels of cortactin and activin A receptors, whereas cells with low cortactin expression were largely unresponsive. Moreover, cortactin depletion abolished activin A-induced migration, transendothelial migration, and organoid colonization. Inhibition of ERK1/2, a major cortactin-activating kinase, similarly blocked activin A-dependent responses. Together, these findings identify a previously unrecognized activin A–ERK1/2–cortactin signaling axis that drives B-ALL dissemination and represents a therapeutic vulnerability for preventing microenvironment-driven relapse.</p>