High cortactin expression in B-cell acute lymphoblastic leukemia is associated with increased transendothelial migration and bone marrow relapse

• Published in: Leukemia 2019-06, Vol.33 (6), p.1337-1348
• Main Authors: Velázquez-Avila, Martha, Balandrán, Juan Carlos, Ramírez-Ramírez, Dalia, Velázquez-Avila, Mirella, Sandoval, Antonio, Felipe-López, Alfonso, Nava, Porfirio, Alvarado-Moreno, José Antonio, Dozal, David, Prieto-Chávez, Jessica L., Schaks, Matthias, Rottner, Klemens, Dorantes-Acosta, Elisa, López-Martínez, Briceida, Schnoor, Michael, Pelayo, Rosana
• Format: Article
• Language: English
• Subjects: 14/19; 38/77; 59; 631/67/1990/283/2125; 631/80; 64/60; 82/51; 82/80; Actin; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adolescent; Animals; Apoptosis; Biomarkers, Tumor - metabolism; Bone cancer; Bone marrow; Bone Marrow Neoplasms - metabolism; Bone Marrow Neoplasms - pathology; Brain; Cancer Research; Care and treatment; Cell adhesion; Cell adhesion & migration; Cell migration; Cell Proliferation; Cerebrospinal fluid; Child; Child, Preschool; Children; Chronic lymphocytic leukemia; Colonization; Cortactin - metabolism; Critical Care Medicine; CXCL12 protein; Diagnostic software; Diagnostic systems; Drug resistance; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Health aspects; Hematology; Humans; Hypoxia; Infant; Infant, Newborn; Infiltration; Intensive; Internal Medicine; Leukemia; Lungs; Lymphatic leukemia; Lymphocytes B; Male; Malignancy; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Nude; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Oncology; Organoids; Patient outcomes; Patients; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Prognosis; Risk factors; Risk groups; Solid tumors; Survival Rate; Transendothelial and Transepithelial Migration; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-018-0333-4

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 cortactin high -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.