急性白血病细胞SHIP基因的突变分析(英文)

Mutation Analysis of SHIP Gene in Acute Leukemia

SHIP (SH2domaincontaininginositol5′ phosphatase)基因主要在造血细胞表达 ,并在造血细胞的发生发育中发挥关键的负调节作用。本研究旨在评价SHIP基因突变在白血病发病中的作用。利用RT PCR、SSCP及DNA序列分析技术检测了 32例急性髓细胞白血病、9例急性淋巴细胞白血病及正常对照骨髓或外周血标本中SHIP基因表达及突变情况。RT PCR显示所有标本中都有SHIP基因表达 ,2 2 % (7/32 )AML和 12 % (1/9)ALL标本中存在SHIP基因的突变 ,其中 1例AML患者发病时标本同时存在 2个错义突变 ,而完全缓解 (CR)后消失 ,而且其发病时的白血病细胞在体外随着IL 3的刺激其Akt的磷酸化明显增加。结论 :本研究首次发现急性白血病细胞中SHIP基因突变 ,提示SHIP基因的突变可能与白血病发病有关 ;在造血细胞中 ,它很可能做为一个抑癌基因通过负性调节PI3K/Akt信号通路发挥作用。

The SH2 domain containing inositol 5′-phosphatase (SHIP) was initially described as a 145 kD protein phosphorylated on tyrosines upon growth factor and cytokine stimulation. SHIP is predominately expressed in hematopoietic cells, and is a crucial negative regulator in the development of hematopoietic cells. To evaluate the role of the SHIP gene in human leukemogenesis,expression and mutation of SHIP gene in bone marrow and /or peripheral blood from 32 patients with acute myeloid leukemia (AML),9 patients with acute lymphoblastic leukemia (ALL),as well as human hematopoietic cell lines were analyzed by reverse transcription-polymerase chain reaction (RT-PCR),single strand conformational polymorphism (SSCP) and sequencing. The RT-PCR showed that all samples expressed SHIP gene. Mutations of SHIP gene were detected in 7 out of 32 AML patients (22%) and one out of 9 ALL patients (12%). Interestingly, two missense mutations that had been observed in one AML patient at diagnosis disappeared after complete remission (CR). In addition,Akt phosphorylation was prolonged and increased following IL-3 stimulation in this patient sample. In conclusion,data of this study demonstrate the mutation of the SHIP gene in acute leukemia for the first time and suggest a possible role of the mutation of this gene in the development of acute leukemia. SHIP serves as a tumor suppressor by negatively regulating the PI3K/Akt signaling pathway in hematopoietic cells.