期刊
LEUKEMIA
卷 30, 期 6, 页码 1246-1254出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.9
关键词
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资金
- Cancer Prevention and Research Institute of Texas (CPRIT) grant
- Leukemia & Lymphoma Society Scholar Award in Clinical Research
- Else-Kroner Forschungskolleg
- German Research Foundation [SFB 1074]
- Forderkreis fur Tumor-und Leukamiekranke Kinder Ulm
- MD Anderson Cancer Center Support Grant [CA016672]
- NCI [CA016672]
- Cancer Research UK [18131] Funding Source: researchfish
Precursor-B-cell receptor (pre-BCR) signaling and spleen tyrosine kinase (SYK) recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacological and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR+ B-ALL, but not other B-ALL subsets, on this signaling pathway. We demonstrate that SYK, PI3K/AKT, FOXO1 and MYC are important downstream mediators of pre-BCR signaling in B-ALL. Furthermore, we define a characteristic immune phenotype and gene expression signature of pre-BCR+ ALL to distinguish them from other B-ALL subsets. These data provide comprehensive new insight into pre-BCR signaling in B-ALL and corroborate pre-BCR signaling and SYK as promising new therapeutic targets in pre-BCR+ B-ALL.
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