Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
Leuk Res. 2012 Mar;36(3):299-306. doi: 10.1016/j.leukres.2011.08.001. Epub 2011 Sep 1.
The cure rate for pediatric patients with B precursor acute lymphoblastic leukemia (pre-B ALL) is steadily improving, however relapses do occur despite initial response to therapy. To identify links between drug resistance and gene deregulation we used oligonucleotide microarray technology and determined in 184 pre-B ALL specimen genes differentially expressed compared to normal CD34(+) specimens. We identified 20 signature genes including CTGF, BMP-2, CXCR4 and IL7R, documented to regulate interactions in the bone marrow. We recorded remarkably similar levels of expression in three independent patient cohorts, and found distinct patterns in cytogenetically defined subgroups of pre-B ALL. The canonical pathways that were affected are involved in inter- and intra-cellular communication, regulating signaling within the microenvironment. We tested experimentally whether interaction with stromal cells conferred protection to four drugs used in current ALL therapy, and demonstrated that bone marrow stromal cells significantly influenced resistance to vincristine and cytosine arabinoside. Compounds designed to block the identified cellular interactions within the bone marrow microenvironment are expected to mobilise the leukemic cells and make them more accessible to contemporary antileukemic agents. The data provide novel insight into the pathobiology of ALL and indicate new therapeutic targets for patients with ALL.
儿童急性 B 前体细胞淋巴细胞白血病（pre-B ALL）患者的治愈率正在稳步提高，但尽管最初对治疗有反应，仍会发生复发。为了确定耐药性与基因失调之间的联系，我们使用寡核苷酸微阵列技术，在 184 个 pre-B ALL 标本中与正常 CD34(+)标本相比，确定了差异表达的基因。我们鉴定了 20 个特征基因，包括 CTGF、BMP-2、CXCR4 和 IL7R，这些基因被证明可以调节骨髓中的相互作用。我们在三个独立的患者队列中记录了非常相似的表达水平，并在细胞遗传学定义的 pre-B ALL 亚组中发现了不同的模式。受影响的经典途径涉及细胞间和细胞内通讯，调节微环境中的信号转导。我们通过实验测试了与基质细胞相互作用是否能赋予当前 ALL 治疗中使用的四种药物耐药性，并证明骨髓基质细胞显著影响长春新碱和阿糖胞苷的耐药性。预计设计用于阻断骨髓微环境中识别出的细胞相互作用的化合物将动员白血病细胞，并使它们更容易受到当代抗白血病药物的影响。这些数据为 ALL 的病理生物学提供了新的见解，并为 ALL 患者指出了新的治疗靶点。
