Nf1 mutant mice with p19ARF gene loss develop accelerated hematopoietic disease resembling acute leukemia with a variable phenotype.
Nf1 mutant mice with p19ARF gene loss develop accelerated hematopoietic disease resembling acute leukemia with a variable phenotype.
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DOI：
10.1002/ajh.22035
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发表时间：
2011-07
影响因子：
12.8
通讯作者：
Largaespada, David A.
中科院分区：
文献类型：
--
作者：
Wiesner, Stephen M.;Geurts, Jennifer L.;Diers, Miechaleen D.;Bergerson, Rachel J.;Hasz, Diane E.;Morgan, Kelly J.;Largaespada, David A.
青少年髓单细胞白血病（JMML）是一种持续进展的骨髓增生/骨髓增生异常（MPD/MDS）造血疾病，在至少三种不同遗传病变之一的患者中更常见，特别是NF1基因丢失和PTPN11和NRAS突变。NF1和PTPN11分别是与I型神经纤维瘤病综合征（NF1综合征）和Noonan综合征相关的分子病变。jml的出现是罕见的；即使在那些易患这些综合征的人群中，继发性遗传事件也可能导致疾病的发展和进展。在NF1综合征中，p53功能丧失是实体肿瘤中常见的事件，但在JMML中并不常见，这表明p53通路可能被这种造血疾病中的其他事件所修饰。本文研究了p19Arf （p19）肿瘤抑制因子在小鼠Nf1基因缺失相关的MPD发展中的可能作用。我们发现p19缺失的Nf1突变造血细胞会加速发生类似于急性白血病的造血疾病，并具有可变表型。这表明p19可能在JMML的发展中发挥作用，对JMML中人类p19同源物（p14ARF）的评估可能提供信息。
Juvenile Myelomonocytic Leukemia (JMML) is a relentlessly progressive myeloproliferative/myelodysplastic (MPD/MDS) hematopoietic disorder more common in patients with any one of at least three distinct genetic lesions, specifically NF1 gene loss and PTPN11 and NRAS mutations. NF1 and PTPN11 are molecular lesions associated with Neurofibromatosis Syndrome Type I (NF1 Syndrome) and Noonan’s Syndrome, respectively. The occurrence of JMML is rare; even among those predisposed with these syndromes to development of disease, and secondary genetic events likely contribute to the development and progression of disease. In NF1 syndrome, loss of p53 function is a common event in solid tumors, but uncommon in JMML, suggesting that the p53 pathway may be modified by other events in this hematopoietic disorder. The work presented here investigates the possible role of the p19Arf (p19) tumor suppressor in development of MPD associated with Nf1 gene loss in mice. We find that Nf1 mutant hematopoietic cells with loss of p19 develop accelerated hematopoietic disease similar to acute leukemia with a variable phenotype. This suggests that p19 may play a role in development of JMML and evaluation of the human p19 homolog (p14ARF) in JMML may be informative.
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