Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Blood. 2010 May 13;115(19):3966-9. doi: 10.1182/blood-2009-09-242107. Epub 2009 Dec 9.
Down syndrome is characterized by multiple phenotypic manifestations associated with trisomy of chromosome 21. The transient myeloproliferative disorder and acute megakaryocytic leukemia associated with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown. Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(17(16))65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion. Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(17(16))65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.
唐氏综合征的特征是多种与 21 号染色体三体相关的表型表现。唐氏综合征相关的短暂骨髓增生异常和急性巨核细胞白血病与转录因子 GATA1 的突变有关；然而，导致这些血液疾病的 21 号染色体三体基因的身份仍然未知。我们使用功能丧失等位基因表明， Erg 基因的特定功能二倍体减少可纠正唐氏综合征 Ts(17(16))65Dn 小鼠模型中骨髓增生的病理和血液学特征，包括巨核细胞增多和祖细胞扩增。我们的数据提供了遗传证据，证明 Erg 三体对于 Ts(17(16))65Dn 小鼠的骨髓增生是必需的，并暗示 ERG 基因剂量的增加可能是 21 号染色体三体的一个关键后果，可能导致唐氏综合征中的恶性血液疾病。
