Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias
Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias
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DOI：
10.1182/blood-2007-10-113068
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发表时间：
2008-05-01
期刊：
影响因子：
20.3
通讯作者：
Haber, Daniel A.
中科院分区：
文献类型：
--
作者：
Kim, Woo Jae;Okimoto, Ross A.;Haber, Daniel A.
神经酰胺是一种脂类第二信使，源于鞘磷脂酶(SMase)对鞘磷脂的水解，参与多种细胞反应，包括生长停滞、分化和细胞凋亡。中性sMase(NSMase)基因Smpd3是神经酰胺生物合成的主要调节者，它与骨的发育缺陷有关；神经酰胺水平的调节与巨噬细胞分化有关，但这一途径尚未直接与人类癌症有关。在对小鼠骨肉瘤模型中导致肿瘤发生的基因复制缺失的基因组筛查中，我们发现了针对Smpd3的体细胞纯合子缺失。SMPD3在缺乏内源性基因的小鼠肿瘤细胞中表达的重建增强了肿瘤坏死因子(TNF)诱导的细胞活力下降。对大量人类肿瘤中高度保守的SMPD3基因的核苷酸序列分析显示，92例急性髓系白血病(AML)中有5例(5%)发生突变，131例急性淋巴细胞性白血病(ALL)中有8例(6%)发生突变，但在其他肿瘤类型中未见突变。在这些突变的一个子集中，功能分析表明蛋白质的稳定性和定位存在缺陷。综上所述，这些观察表明神经酰胺途径的中断可能导致人类白血病的一个子集。
Ceramide is a lipid second messenger derived from the hydrolysis of sphingomyelin by sphingomyelinases (SMases) and implicated in diverse cellular responses, including growth arrest, differentiation, and apoptosis. Defects in the neutral SMase (nSMase) gene Smpd3, the primary regulator of ceramide biosynthesis, are responsible for developmental defects of bone; regulation of ceramide levels have been implicated in macrophage differentiation, but this pathway has not been directly implicated in human cancer. In a genomic screen for gene copy losses contributing to tumorigenesis in a mouse osteosarcoma model, we identified a somatic homozygous deletion specifically targeting Smpd3. Reconstitution of SMPD3 expression in mouse tumor cells lacking the endogenous gene enhanced tumor necrosis factor (TNF)-induced reduction of cell viability. Nucleotide sequencing of the highly conserved SMPD3 gene in a large panel of human cancers revealed mutations in 5 (5%) of 92 acute myeloid leukemias (AMLs) and 8 (6%) of 131 acute lymphoid leukemias (ALLs), but not in other tumor types. In a subset of these mutations, functional analysis indicated defects in protein stability and localization. Taken together, these observations suggest that disruption of the ceramide pathway may contribute to a subset of human leukemias.