Williams R T, Sherr C J
Departments of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cold Spring Harb Symp Quant Biol. 2008;73:461-7. doi: 10.1101/sqb.2008.73.039. Epub 2008 Nov 21.
Senescence and apoptosis programs governed by the Rb and p53 signaling networks can counter tissue stem cell self-renewal. A master regulator of Rb and p53 is the INK4-ARF (CDKN2A/B) locus that encodes two CDK inhibitors, p16(INK4A) and p15(INK4B), that maintain Rb in its active, hypophosphorylated form, and p14(ARF) (p19(Arf) in mice), that inhibits Mdm2 and activates p53. The INK4-ARF genes are epigenetically silenced in hematopoietic stem cells but become poised to respond to oncogenic stress as blood cells differentiate. Inactivation of INK4-ARF endows differentiated cells with an inappropriate self-renewal capacity, a defining feature of cancer cells. In BCR-ABL-induced (Philadelphia chromosome-positive [Ph(+)]) leukemias, INK4-ARF deletions frequently occur in clinically aggressive acute lymphoblastic leukemias (Ph(+) ALLs) but are not seen in more indolent Ph(+) chronic myelogenous leukemia (CML) or in CML myeloid blast crisis. Mouse modeling of Ph(+) ALL reveals that Arf inactivation attenuates responsiveness to targeted BCR-ABL kinase inhibitors, enhances the maintenance of leukemia-initiating cells within the hematopoietic microenvironment, and facilitates the emergence of malignant clones that harbor drug-resistant BCR-ABL kinase mutations. Thus, although BCR-ABL mutations typify drug resistance in both CML and Ph(+) ALL, loss of INK4-ARF in Ph(+) ALL enhances disease aggressiveness and undermines the salutary effects of targeted therapy.
由Rb和p53信号网络调控的衰老和凋亡程序可对抗组织干细胞的自我更新。Rb和p53的一个主要调节因子是INK4-ARF（CDKN2A/B）基因座，它编码两种细胞周期蛋白依赖性激酶（CDK）抑制剂，即p16（INK4A）和p15（INK4B），它们使Rb维持在其活性的低磷酸化形式，以及p14（ARF）（小鼠中的p19（Arf）），它抑制Mdm2并激活p53。INK4-ARF基因在造血干细胞中通过表观遗传方式沉默，但随着血细胞分化，它们会随时准备对致癌应激作出反应。INK4-ARF的失活赋予分化细胞不适当的自我更新能力，这是癌细胞的一个决定性特征。在BCR-ABL诱导的（费城染色体阳性[Ph(+)]）白血病中，INK4-ARF缺失经常发生在临床侵袭性急性淋巴细胞白血病（Ph(+) ALL）中，但在惰性更强的Ph(+)慢性粒细胞白血病（CML）或CML髓系原始细胞危象中未见。Ph(+) ALL的小鼠模型显示，Arf失活会减弱对靶向BCR-ABL激酶抑制剂的反应性，增强造血微环境中白血病起始细胞的维持，并促进携带耐药性BCR-ABL激酶突变的恶性克隆的出现。因此，尽管BCR-ABL突变是CML和Ph(+) ALL耐药的典型特征，但Ph(+) ALL中INK4-ARF的缺失会增强疾病的侵袭性，并削弱靶向治疗的有益效果。
