期刊
LEUKEMIA
卷 33, 期 6, 页码 1337-1348出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41375-018-0333-4
关键词
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资金
- Mexican Council for Science and Technology CONACyT [FOSISSS 233395, 2015-1-261848]
- Mexican Institute for Social Security (IMSS) [FIS/IMSS/PROT/G14/1289]
- Helmholtz Society
- Career-inImmunology-Fellowship of the American Association of Immunologists (AAI)
- Royal Society [NAF/R1/180017]
- CONACyT
- IMSS
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 BALL. 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.
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