MNI overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML
MNI overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML
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DOI：
10.1182/blood-2007-03-080523
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发表时间：
2007-09-01
期刊：
影响因子：
20.3
通讯作者：
Humphries, R. Keith
中科院分区：
文献类型：
--
作者：
Heuser, Michael;Argiropoulos, Bob;Humphries, R. Keith
野生型MN 1的过表达是细胞遗传学正常的急性髓性白血病（AML）患者的一个不良预后因素。我们评估了MN 1是否在白血病发生中发挥功能性作用。我们证明，使用逆转录病毒基因转移和骨髓（BM）移植，MN 1过表达迅速诱导小鼠致命的AML。插入突变和染色体不稳定性被排除为继发性畸变。MN 1在体外增加了对全反式维甲酸（ATRA）诱导的细胞周期停滞和分化的抵抗力超过3000倍。分化阻滞可以通过将转录激活因子（VP 16）融合到MN 1而释放，而不影响使BM细胞永生化的能力，这表明MN 1通过转录抑制来阻滞分化。然后，我们评估了AML患者（不包括M3-AML）中MN 1表达水平是否与在治疗方案AMLHD 98-B中统一治疗的老年患者对ATRA治疗的耐药性相关。值得注意的是，接受ATRA治疗的MN 1低表达患者的无事件生存率（P = 0.008）和总生存率（P = 0.04）显著高于MN 1低表达且无ATRA或MN 1高表达且有或无ATRA的患者。MN 1是造血中一种独特的癌基因，既能促进增殖/自我更新，又能阻断分化，可能成为AML治疗中的一种预测标志物。
Overexpression of wild-type MN1 is a negative prognostic factor in patients with acute myelold leukemia (AML) with normal cytogenetics. We evaluated whether MN1 plays a functional role in leukemogenesis. We demonstrate using retroviral gene transfer and bone marrow (BM) transplantation that MN1 overexpression rapidly induces lethal AML in mice. Insertional mutagenesis and chromosomal instability were ruled out as secondary aberrations. MN1 increased resistance to all-trans retinoic acid(ATRA)-induced cell-cycle arrest and differentiation by more than 3000-fold in vitro. The differentiation block could be released by fusion of a transcriptional activator (VP16) to MN1 without affecting the ability to immortalize BM cells, suggesting that MN1 blocks differentiation by transcriptional repression. We then evaluated whether MN1 expression levels in patients with AML (excluding M3-AML) correlated with resistance to ATRA treatment in elderly patients uniformly treated within treatment protocol AMLHD98-B. Strikingly, patients with low MN1 expression who received ATRA had a significantly prolonged event-free (P = .008) and overall (P = .04) survival compared with patients with either low MN1 expression and no ATRA, or high MN1 expression with or without ATRA. MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment.