Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Blood. 2012 Oct 11;120(15):3089-97. doi: 10.1182/blood-2012-01-405332. Epub 2012 Aug 27.
The nucleoporin gene NUP98 is fused to several genes including HOXD13 in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic myeloid leukemia, blast crisis. Genetically engineered mice that express a NUP98-HOXD13 (NHD13) transgene (Tg) display the phenotypic features of MDS, including cytopenias, bone marrow dysplasia, and transformation to acute leukemia. Here we show that short-term treatment with the p53 inhibitor Pifithrin-α partially and transiently rescued the myeloid and lymphoid abnormalities found in NHD13(+) Tg mice, with no improvement in the anemia, while the genetic deletion of 2 alleles of p53 rescued both the myeloid progenitor cell and long-term hematopoietic stem cell compartments. Nonetheless, loss of one or both alleles of p53 did not rescue the MDS phenotype, but instead exacerbated the MDS phenotype and accelerated the development of acute myeloid leukemia. Our studies suggest that while targeting p53 may transiently improve hematopoiesis in MDS, over the long-term, it has detrimental effects, raising caution about abrogating its function to treat the cytopenias that accompany this disease.
核孔蛋白基因 NUP98 与几种基因融合，包括骨髓增生异常综合征 (MDS)、急性髓系白血病和慢性髓系白血病急变期患者中的 HOXD13。表达 NUP98-HOXD13（NHD13）转基因 (Tg) 的基因工程小鼠表现出 MDS 的表型特征，包括细胞减少症、骨髓增生异常和向急性白血病转化。在这里，我们表明，用 p53 抑制剂 Pifithrin-α 短期治疗可部分和短暂地纠正 NHD13(+)Tg 小鼠中发现的髓系和淋巴系异常，而对贫血没有改善，而 p53 的 2 个等位基因的遗传缺失则可纠正髓系祖细胞和长期造血干细胞区室。尽管如此，p53 的一个或两个等位基因的缺失并不能挽救 MDS 表型，反而加剧了 MDS 表型并加速了急性髓系白血病的发展。我们的研究表明，虽然靶向 p53 可能会暂时改善 MDS 中的造血功能，但从长远来看，它会产生有害影响，这就引发了对其功能进行干预以治疗这种疾病伴随的细胞减少症的警惕。
