Abstract
Cancer is a major cause of death in children worldwide, with B-lineage cell acute lymphoblastic leukemia (B-ALL) being the most frequent childhood malignancy. Relapse, treatment failure and organ infiltration worsen the prognosis, warranting a better understanding of the implicated mechanisms. Cortactin is an actin-binding protein involved in cell adhesion and migration that is overexpressed in many solid tumors and in adult B-cell chronic lymphocytic leukemia. Here, we investigated cortactin expression and potential impact on infiltration and disease prognosis in childhood B-ALL. B-ALL cell lines and precursor cells from bone marrow (BM) and cerebrospinal fluid (CSF) of B-ALL patients indeed overexpressed cortactin. In CXCL12-induced transendothelial migration assays, transmigrated B-ALL cells had highest cortactin expression. In xenotransplantation models, only cortactinhigh-leukemic cells infiltrated lungs, brain, and testis; and they colonized more easily hypoxic BM organoids. Importantly, cortactin-depleted B-ALL cells were significantly less efficient in transendothelial migration, organ infiltration and BM colonization. Clinical data highlighted a significant correlation between high cortactin levels and BM relapse in drug-resistant high-risk B-ALL patients. Our results emphasize the importance of cortactin in B-ALL organ infiltration and BM relapse and its potential as diagnostic tool to identify high-risk patients and optimize their treatments.
Highlights
Childhood cancer is a global health priority [1,2,3], with leukemia remaining a leading cause of morbidity and mortality in children worldwide, showing incidence rates of 140.6 per million new cases per year in ages of 0–14 [1]
We analyzed the mRNA levels of the actinbinding proteins (ABP) cortactin and hematopoietic cell-specific lyn substrate 1 (HS1) in the Pre B-cell line REH isolated from a B-lineage cell acute lymphoblastic leukemia (B-ALL cells from newly diagnosed (ALL)) relapse patient
PCR for cortactin and HS1 was performed with cDNA from REH cells or umbilical cord blood (UCB)-derived CD19+-cells as control
Summary
Childhood cancer is a global health priority [1,2,3], with leukemia remaining a leading cause of morbidity and mortality in children worldwide, showing incidence rates of 140.6 per million new cases per year in ages of 0–14 [1]. Extended author information available on the last page of the article lymphoblastic leukemia (B-ALL) represents 73–85% of total cases [4]. Transendothelial migration (TEM), and homing may trigger organ infiltration [8, 9]. Cortactin and its homolog hematopoietic cell-specific lyn substrate 1 (HS1) are actinbinding proteins (ABP) facilitating cell adhesion and migration [10].
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