Inactivation of the Cdkn2a locus cooperates with HMGA1 to drive T-cell leukemogenesis
Inactivation of the Cdkn2a locus cooperates with HMGA1 to drive T-cell leukemogenesis
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DOI：
10.3109/10428194.2013.764422
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发表时间：
2013-08-01
影响因子：
2.6
通讯作者：
Resar, Linda
中科院分区：
文献类型：
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作者：
Di Cello, Francescopaolo;Dhara, Surajit;Resar, Linda
t细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性白血病，与b系ALL相比复发率高。我们之前的研究表明，HMGA1a转基因小鼠发生侵袭性T-ALL，表明HMGA1在体内引起白血病转化。HMGA1也在胚胎干细胞、造血干细胞和多种难治性人类癌症中高度表达。CDKN2A肿瘤抑制位点的破坏发生在大多数T-ALL病例中，并被认为有助于白血病转化。为了确定CDKN2A的功能丧失是否与HMGA1在T-ALL中协同作用，我们将HMGA1a转基因基因交叉到CDKN2A零背景上。我们发现在HMGA1a转基因Cdkn2a缺失小鼠中T-ALL明显加速。此外，这些小鼠重现了人类T-ALL的显著临床和病理特征。HMGA1在人类T-ALL中也高度过表达。这些发现表明HMGA1在T-ALL中起致病作用，可能是一个合理的治疗靶点。
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia with high relapse rates compared to B-lineage ALL. We previously showed that HMGA1a transgenic mice develop aggressive T-ALL, indicating that HMGA1 causes leukemic transformation in vivo. HMGA1 is also highly expressed in embryonic stem cells, hematopoietic stem cells and diverse, refractory human cancers. Disruption of the CDKN2A tumor suppressor locus occurs in most cases of T-ALL and is thought to contribute to leukemic transformation. To determine whether loss of function of CDKN2A cooperates with HMGA1 in T-ALL, we crossed HMGA1a transgenics onto a Cdkn2a null background. We discovered that T-ALL is markedly accelerated in HMGA1a transgenic Cdkn2a null mice. In addition, these mice recapitulate salient clinical and pathologic features of human T-ALL. HMGA1 is also highly overexpressed in human T-ALL. These findings suggest that HMGA1 plays a causative role in T-ALL and could represent a rational therapeutic target.