Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival
Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival
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DOI：
10.1182/blood-2002-05-1519
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发表时间：
2003-02-01
期刊：
影响因子：
20.3
通讯作者：
Freedman, AS
中科院分区：
文献类型：
--
作者：
Astier, AL;Xu, RH;Freedman, AS
B细胞和淋巴组织微环境中基质细胞之间的物理相互作用对正常和恶性B细胞的存活至关重要。它们主要由B细胞上表达的整联蛋白和基质细胞上的反受体介导。具体地，α 4 β 1整联蛋白接合从生理或药物诱导的凋亡中拯救B细胞。因此，为了了解整合素阻止白血病B细胞凋亡的机制，我们比较了血清饥饿前体B白血病细胞中β 1-整合素与纤连蛋白（Fn）连接或多聚赖氨酸粘附诱导的时间基因表达谱。在筛选出的38个差异表达基因中，通过实时定量聚合酶链反应（RT-Q-PCR）验证了6个与粘附（VAV 2、EPB 41 L1、CORO 1A）、增殖（FRAP 1、CCT 4）和细胞间通讯（GJB 3）相关的基因。基因表达调节也可以在蛋白质水平上验证5个其他基因。我们发现，整联蛋白刺激上调FBI-1的表达，但抑制CD 79 a，c-Fos，c-caspase 7诱导细胞凋亡时。我们进一步证明，Fn刺激也抑制caspase 3的激活，但增加XIAP和生存素的表达。此外，整联蛋白刺激还防止多柔比星诱导的半胱天冬酶活化。因此，我们确定了受人前体B白血病细胞粘附调节的基因，这些基因调节增殖和凋亡，突出了新的途径，这些途径可能为未来旨在靶向白血病细胞凋亡的治疗提供见解。(C)2003年，美国血液学会。
The physical interactions between B cells and stromal cells from the lymphoid tissue microenvironment are critical to the survival of normal and malignant B cells. They are principally mediated by integrins expressed on B cells and counterreceptors on stromal cells. Specifically, alpha4beta1 integrin engagement rescues B cells from physiological or drug-induced apoptosis. Therefore, in order to understand the mechanisms by which integrins prevent apoptosis in leukemia B cells, we compared the temporal gene expression profiles induced by beta1-integrin ligation with fibronectin (Fn) or adhesion by poly-L-Lysine in serum-starved precursor B leukemia cells. Among the 38 selected differentially expressed genes, 6 genes involved in adhesion (VAV2, EPB41L1, CORO1A), proliferation (FRAP1, CCT4), and intercellular communication (GJB3) were validated by real-time quantitative polymerase chain reaction (RT-Q-PCR). Gene expression modulation could also be validated at the protein level for 5 other genes. We show that integrin stimulation up-regulated FBI-1 expression but inhibited CD79a, Requiem, c-Fos, and caspase 7 induction when the cells underwent apoptosis. We further demonstrate that Fn stimulation also inhibits caspase 3 activation but increases XIAP and survivin expression. Moreover, integrin stimulation also prevents caspase activation induced by doxorubicin. Therefore, we identified genes modulated by adhesion of human precursor B leukemia cells that regulate proliferation and apoptosis, highlighting new pathways that might provide insights into future therapy aiming at targeting apoptosis of leukemia cells. (C) 2003 by The American Society of Hematology.