Division of Pediatric Hematology-Oncology, Vanderbilt University, Nashville, TN, USA.
Exp Hematol. 2013 Apr;41(4):377-86. doi: 10.1016/j.exphem.2012.11.006. Epub 2012 Nov 23.
Activating mutations of NOTCH1 and deletion of the INK4A-ARF (CDKN2A) tumor suppressor locus are two of the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL). In a murine model of T-ALL induced by the intracellular domain of Notch1 (ICN1), the genetic interaction between ICN1 signaling and Arf inactivation is developmentally stage-specific, with a more pronounced requirement for Arf deletion in thymocytes than in bone marrow precursors targeted for transformation. In the thymus, the target cell for transformation is a CD4 and CD8 double-negative progenitor that undergoes T cell receptor beta-chain rearrangement, a cell type in which polycomb silencing of Ink4a-Arf is normally requisite. Epigenetic remodeling during tumor progression licenses Arf as a tumor suppressor and in turn provides the selective pressure for Ink4a-Arf deletion in clonal T-ALLs that emerge.
NOTCH1 激活突变和 INK4A-ARF(CDKN2A)肿瘤抑制基因座缺失是 T 细胞急性淋巴细胞白血病(T-ALL)中最常见的两种遗传改变。在 Notch1 细胞内结构域(ICN1)诱导的 T-ALL 小鼠模型中，ICN1 信号和 Arf 失活之间的遗传相互作用具有发育阶段特异性，在胸腺细胞中，Arf 缺失的要求比骨髓前体转化的要求更为明显。在胸腺中，转化的靶细胞是经历 T 细胞受体β链重排的 CD4 和 CD8 双阴性祖细胞，该细胞类型中通常需要多梳抑制 Ink4a-Arf。肿瘤进展过程中的表观遗传重塑将 Arf 作为肿瘤抑制因子，并反过来为克隆性 T-ALL 中 Ink4a-Arf 的缺失提供选择性压力。
