期刊
BLOOD
卷 123, 期 20, 页码 3116-3127出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-05-499970
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资金
- Scottish Senior Clinical Fellowship (Scottish Funding Council)
- Kay Kendall Leukaemia Fund [KKL454]
- Royal Hospital for Sick Children
- Edinburgh Haematology Fund
- Chief Scientist Office [SCD/08]
- Medical Research Council [G0901113]
- MRC [G0901113] Funding Source: UKRI
- Chief Scientist Office [SCD/08] Funding Source: researchfish
- Medical Research Council [G0901113] Funding Source: researchfish
- National Institute for Health Research [RP-PG-0310-1003] Funding Source: researchfish
Genome-wide association studies have consistently implicated the interleukin-15 (IL-15) gene in acute lymphoblastic leukemia (ALL) biology, including associations with disease susceptibility, and increased risk of central nervous system (CNS) involvement. However, whether pre-BALL blasts directly respond to IL-15 is unknown. Here, we show that most pre-BALL primary samples and cell lines express IL-15 and components of its receptor and that primary pre-B ALL cells show increased growth in culture in response to IL-15. Investigation of mechanisms of action using IL-15-responsive SD-1 cells shows this growth advantage is maximal under low-serum conditions, mimicking those found in cerebrospinal fluid. IL-15 also upregulates PSGL-1 and CXCR3, molecules associated with CNS trafficking. Investigation of downstream signaling pathways indicates that IL-15 induces signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinase (ERK) 1/2, and to a lesser extent phosphatidylinositol 3-kinase (PI3K) and nuclear factor kappa B (NF-kappa B) phosphorylation. The IL-15-mediated growth advantage is abolished by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), PI3K, and NF-kappa B inhibitors but preserved in the presence of STAT5 inhibition. Together, these observations provide a mechanistic link between increased levels of IL-15 expression and leukemogenesis, high-risk disease, and CNS relapse and suggest potential therapeutic targets.
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