Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice.
Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice.
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DOI：
10.1371/journal.pone.0074864
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Naoe T
中科院分区：
文献类型：
--
作者：
Yamamoto K;Tsuzuki S;Minami Y;Yamamoto Y;Abe A;Ohshima K;Seto M;Naoe T
在ABL激酶抑制剂出现后，慢性粒细胞白血病（CML）慢性期（CP）患者已成功治疗，但一旦进展到急变期（BC），预后变得令人沮丧。虽然进展的机制在很大程度上是未知的，但最近的研究表明造血关键分子的改变，如AML 1/RUNX 1。我们对13例BC病例的分析显示，3例有AML 1突变，野生型（wt.）AML 1在BC组较CP组升高。使用小鼠造血细胞对代表性AML 1突变体进行的功能分析揭示了一些（但不是全部）突变体对BC表型的可能贡献。具体地说，K83 Q和R139 G突变体（但R80 C和D171 N突变体均不存在）使表达BCR-ABL的细胞在无精氨酸的培养物中比仅表达BCR-ABL的对照细胞具有生长优势，并且如此生长的细胞在静脉内转移时杀死小鼠。出乎意料的是，wt.AML1的表现与K83 Q和R139 G突变体相似。在骨髓移植试验中，K83 Q和wt. AML 1 s诱导了胚样细胞的出现。总体研究结果表明，AML 1的功能改变的一些，但不是所有的突变体，和表达的升高wt. AML 1 CML的疾病进展的作用。
Patients in the chronic phase (CP) of chronic myelogenous leukemia (CML) have been treated successfully following the advent of ABL kinase inhibitors, but once they progress to the blast crisis (BC) phase the prognosis becomes dismal. Although mechanisms underlying the progression are largely unknown, recent studies revealed the presence of alterations of key molecules for hematopoiesis, such as AML1/RUNX1. Our analysis of 13 BC cases revealed that three cases had AML1 mutations and the transcript levels of wild-type (wt.) AML1 were elevated in BC compared with CP. Functional analysis of representative AML1 mutants using mouse hematopoietic cells revealed the possible contribution of some, but not all, mutants for the BC-phenotype. Specifically, K83Q and R139G, but neither R80C nor D171N mutants, conferred upon BCR-ABL-expressing cells a growth advantage over BCR-ABL-alone control cells in cytokine-free culture, and the cells thus grown killed mice upon intravenous transfer. Unexpectedly, wt.AML1 behaved similarly to K83Q and R139G mutants. In a bone marrow transplantation assay, K83Q and wt.AML1s induced the emergence of blast-like cells. The overall findings suggest the roles of altered functions of AML1 imposed by some, but not all, mutants, and the elevated expression of wt.AML1 for the disease progression of CML.
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影响因子：
11.4
作者：
MITANI, K;OGAWA, S;HIRAI, H
通讯作者：
HIRAI, H
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
82.9
作者：
Ichikawa, M;Asai, T;Kurokawa, M
通讯作者：
Kurokawa, M
DOI：
10.3324/haematol.2011.041053
发表时间：
2011-09-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Nakagawa, Masao;Tsuzuki, Shinobu;Seto, Masao
通讯作者：
Seto, Masao
影响因子：
20.3
作者：
Hamelin, V;Letourneux, C;Gaudry, M
通讯作者：
Gaudry, M