Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.
Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.
复制标题
DOI：
10.1084/jem.20121343
复制
发表时间：
2012-10-22
期刊：
影响因子：
--
通讯作者：
Mercher T
中科院分区：
文献类型：
--
作者：
Thiollier C;Lopez CK;Gerby B;Ignacimouttou C;Poglio S;Duffourd Y;Guégan J;Rivera-Munoz P;Bluteau O;Mabialah V;Diop M;Wen Q;Petit A;Bauchet AL;Reinhardt D;Bornhauser B;Gautheret D;Lecluse Y;Landman-Parker J;Radford I;Vainchenker W;Dastugue N;de Botton S;Dessen P;Bourquin JP;Crispino JD;Ballerini P;Bernard OA;Pflumio F;Mercher T
在31%的非唐氏综合征AMKL中鉴定出CBFA2T3-GLIS2融合基因。急性巨核母细胞白血病（AMKL）是一种异质性疾病，通常与预后不良有关。基因表达谱表明存在不同的分子亚群，并且在过去几年中已经确定了一些遗传改变，包括与GATA1突变相关的t(1;22)（p13;q13）和21三体。然而，大多数患者不存在已知的突变，并且对原发性患者白血病细胞的有限获取阻碍了新治疗策略的有效开发。在这项研究中，使用异种移植方法，我们在免疫缺陷小鼠中模拟了人类儿科AMKL。高通量RNA测序分析确定了定义新分子亚群的复发融合基因。一个亚组患者表现为MLL或NUP98融合基因，导致HOX A簇基因上调。在31%的非唐氏综合征AMKL的另一个亚群中发现了一种新的CBFA2T3-GLIS2融合基因，该基因由16号染色体的隐性倒置产生，并与Hedgehog通路激活的基因表达特征密切相关。这些分子数据为患者的诊断和随访提供了有用的标记物。最后，我们发现AMKL异种移植模型构成了一个相关的体内临床前筛选平台，以验证Aurora a激酶抑制剂等新疗法的有效性。
A CBFA2T3-GLIS2 fusion gene was identified in 31% of non–Down syndrome AMKL. Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non–Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors.
登录
查看更多内容
影响因子：
4.6
作者：
Craven, SE;Lim, KC;Rosenthal, A
通讯作者：
Rosenthal, A
DOI：
10.1073/pnas.0511150103
发表时间：
2006-02-28
影响因子：
11.1
作者：
Bourquin, JP;Subramanian, A;Orkin, SH
通讯作者：
Orkin, SH
影响因子：
20.3
作者：
Dastugue, N;Lafage-Pochitaloff, M;Berger, R
通讯作者：
Berger, R
影响因子：
3.7
作者：
Mercher, T;Coniat, MB;Berger, R
通讯作者：
Berger, R
影响因子：
2
作者：
Kang HS;ZeRuth G;Lichti-Kaiser K;Vasanth S;Yin Z;Kim YS;Jetten AM
通讯作者：
Jetten AM