PDF(Pubmed)
Abstract：
BACKGROUND: Adhesion of cancer cells to extracellular matrix laminin through the integrin superfamily reportedly induces drug resistance. Heterodimers of integrin α6 (CD49f) with integrin β1 (CD29) or β4 (CD104) are major functional receptors for laminin. Higher CD49f expression is reportedly associated with a poorer response to induction therapy in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Moreover, a xenograft mouse model transplanted with primary BCP-ALL cells revealed that neutralized antibody against CD49f improved survival after chemotherapy.
OBJECTIVE: Considering the poor outcomes in Philadelphia chromosome (Ph)-positive ALL treated with conventional chemotherapy without tyrosine kinase inhibitors, we sought to investigate an involvement of the laminin adhesion.
RESULTS: Ph-positive ALL cell lines expressed the highest levels of CD49f among the BCP-ALL cell lines with representative translocations, while CD29 and CD104 were ubiquitously expressed in BCP-ALL cell lines. The association of Ph-positive ALL with high levels of CD49f gene expression was also confirmed in two databases of childhood ALL cohorts. Ph-positive ALL cell lines attached to laminin and their laminin-binding properties were disrupted by blocking antibodies against CD49f and CD29 but not CD104. The cell surface expression of CD49f, but not CD29 and CD104, was downregulated by imatinib treatment in Ph-positive ALL cell lines, but not in their T315I-acquired sublines. Consistently, the laminin-binding properties were disrupted by the imatinib pre-treatment in the Ph-positive ALL cell line, but not in its T315I-acquired subline.
CONCLUSIONS: BCR::ABL1 plays an essential role in the laminin adhesion of Ph-positive ALL cells through upregulation of CD49f.
OBJECTIVE: Considering the poor outcomes in Philadelphia chromosome (Ph)-positive ALL treated with conventional chemotherapy without tyrosine kinase inhibitors, we sought to investigate an involvement of the laminin adhesion.
RESULTS: Ph-positive ALL cell lines expressed the highest levels of CD49f among the BCP-ALL cell lines with representative translocations, while CD29 and CD104 were ubiquitously expressed in BCP-ALL cell lines. The association of Ph-positive ALL with high levels of CD49f gene expression was also confirmed in two databases of childhood ALL cohorts. Ph-positive ALL cell lines attached to laminin and their laminin-binding properties were disrupted by blocking antibodies against CD49f and CD29 but not CD104. The cell surface expression of CD49f, but not CD29 and CD104, was downregulated by imatinib treatment in Ph-positive ALL cell lines, but not in their T315I-acquired sublines. Consistently, the laminin-binding properties were disrupted by the imatinib pre-treatment in the Ph-positive ALL cell line, but not in its T315I-acquired subline.
CONCLUSIONS: BCR::ABL1 plays an essential role in the laminin adhesion of Ph-positive ALL cells through upregulation of CD49f.
摘要：
背景：据报道，癌细胞通过整联蛋白超家族与细胞外基质层粘连蛋白的粘附会诱导耐药性。整联蛋白α6(CD49f)与整联蛋白β1(CD29)或β4(CD104)的异二聚体是层粘连蛋白的主要功能受体。据报道，较高的CD49f表达与儿童B细胞前体急性淋巴细胞白血病（BCP-ALL）对诱导治疗的反应较差有关。此外，移植原代BCP-ALL细胞的异种移植小鼠模型显示,抗CD49f的中和抗体改善了化疗后的存活率.
目的：考虑到费城染色体（Ph）阳性ALL接受常规化疗而不使用酪氨酸激酶抑制剂治疗的不良结局，我们试图调查层粘连蛋白粘附的参与。
结果：Ph阳性ALL细胞系在具有代表性易位的BCP-ALL细胞系中表达最高水平的CD49f，而CD29和CD104在BCP-ALL细胞系中普遍表达。Ph阳性ALL与高水平CD49f基因表达的关联也在儿童ALL队列的两个数据库中得到证实。通过阻断针对CD49f和CD29但不针对CD104的抗体来破坏附着于层粘连蛋白的Ph阳性ALL细胞系及其层粘连蛋白结合特性。细胞表面表达CD49f,而不是CD29和CD104，在Ph阳性ALL细胞系中通过伊马替尼治疗下调，但不是在他们获得的T315I子线。始终如一，在Ph阳性ALL细胞系中，通过伊马替尼预处理破坏了层粘连蛋白结合特性，但不是在其T315I收购的子线。
结论：BCR::ABL1通过上调CD49f在Ph阳性ALL细胞的层粘连蛋白粘附中起重要作用。
目的：考虑到费城染色体（Ph）阳性ALL接受常规化疗而不使用酪氨酸激酶抑制剂治疗的不良结局，我们试图调查层粘连蛋白粘附的参与。
结果：Ph阳性ALL细胞系在具有代表性易位的BCP-ALL细胞系中表达最高水平的CD49f，而CD29和CD104在BCP-ALL细胞系中普遍表达。Ph阳性ALL与高水平CD49f基因表达的关联也在儿童ALL队列的两个数据库中得到证实。通过阻断针对CD49f和CD29但不针对CD104的抗体来破坏附着于层粘连蛋白的Ph阳性ALL细胞系及其层粘连蛋白结合特性。细胞表面表达CD49f,而不是CD29和CD104，在Ph阳性ALL细胞系中通过伊马替尼治疗下调，但不是在他们获得的T315I子线。始终如一，在Ph阳性ALL细胞系中，通过伊马替尼预处理破坏了层粘连蛋白结合特性，但不是在其T315I收购的子线。
结论：BCR::ABL1通过上调CD49f在Ph阳性ALL细胞的层粘连蛋白粘附中起重要作用。
