Estes David A, Lovato Debbie M, Khawaja Hadya M, Winter Stuart S, Larson Richard S
Department of Pathology, University of New Mexico Cancer Research and Treatment Center, Albuquerque, NM 87112, USA.
Br J Haematol. 2007 Oct;139(1):20-30. doi: 10.1111/j.1365-2141.2007.06763.x.
Acquired drug resistance eventually leads to treatment failure in T-cell acute lymphoblastic leukaemia (T-ALL). Immunophenotypic and cytogenetic heterogeneities within T-ALL influence susceptibility to cytotoxic therapy, and little is known about the mechanisms of drug resistance at specific stages of T-cell ontogeny. We developed tolerance to therapeutic concentrations of daunorubicin (DNR) and L-asparaginase (L-asp) in Jurkat (CD1a(-), sCD3(+)) and Sup T1 (CD1a(+), sCD3(-)) cell lines, having respective 'mature' and 'cortical' stages of developmental arrest. DNR resistant cells acquired multidrug resistance: 310-fold increased resistance to vincristine (VCR) and a 120-fold increased resistance to prednisolone (PRED). Microarray analysis identified upregulation of asparagine synthetase (ASNS) and argininosuccinate synthase 1 (ASS1) to cell lines with acquired resistance to L-asp, and in the case of DNR, upregulation of ATP-binding cassette B1 (ABCB1). Suppression of ABCB1, ASNS and ASS1 by RNA interference revealed their functional relevance to acquired drug resistance. Expression profiling of these genes in 80 T-ALL patients showed correlation with treatment response. This study expands the pool of available drug resistant cell lines having cortical and mature stages of developmental arrest, introduces three new drug resistant T-ALL cell lines, and identifies gene interactions leading to L-asp and DNR resistance.
获得性耐药最终会导致T细胞急性淋巴细胞白血病（T-ALL）治疗失败。T-ALL内的免疫表型和细胞遗传学异质性会影响细胞毒性疗法的敏感性，而对于T细胞个体发育特定阶段的耐药机制知之甚少。我们在Jurkat（CD1a(-)，sCD3(+)）和Sup T1（CD1a(+)，sCD3(-)）细胞系中诱导出了对治疗浓度柔红霉素（DNR）和L-天冬酰胺酶（L-asp）的耐受性，这两种细胞系分别处于发育停滞的“成熟”和“皮质”阶段。耐DNR细胞获得了多药耐药性：对长春新碱（VCR）的耐药性增加了310倍，对泼尼松龙（PRED）的耐药性增加了120倍。基因芯片分析发现，对L-asp获得耐药性的细胞系中，天冬酰胺合成酶（ASNS）和精氨琥珀酸合成酶1（ASS1）上调；而对于DNR，ATP结合盒转运体B1（ABCB1）上调。RNA干扰抑制ABCB1、ASNS和ASS1后，揭示了它们与获得性耐药的功能相关性。在80例T-ALL患者中对这些基因进行表达谱分析，结果显示其与治疗反应相关。本研究扩充了具有皮质和成熟阶段发育停滞的可用耐药细胞系库，引入了三种新的耐药T-ALL细胞系，并确定了导致对L-asp和DNR耐药的基因相互作用。
