期刊
BLOOD
卷 113, 期 14, 页码 3314-3322出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-04-154310
关键词
-
类别
资金
- G. Harold and Leila Y. Mathers Charitable Foundation
- National Institutes of Health (NIH)/National Cancer Institute [CA105152]
- Leukemia & Lymphoma Society (White Plains, NY) Translational Research
- Dr Ralph and Marian Faulk Medical Research Trust (Barrington, IL
- NIH/NCI [CA105049, HL087188]
Chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene produce chimeric proteins that cause abnormal expression of a subset of HOX genes and leukemia development. Here, we show that MLL normally regulates expression of mir-196b, a hematopoietic microRNA located within the HoxA cluster, in a pattern similar to that of the surrounding 5' Hox genes, Hoxa9 and Hoxa10, during embryonic stem (ES) cell differentiation. Within the hematopoietic lineage, mir-196b is most abundant in short-term hematopoietic stem cells and is down-regulated in more differentiated hematopoietic cells. Leukemogenic MLL fusion proteins cause overexpression of mir-196b, while treatment of MLL-AF9 transformed bone marrow cells with mir-196-specific antagomir abrogates their replating potential in methylcellulose. This demonstrates that mir-196b function is necessary for MLL fusion-mediated immortalization. Furthermore, overexpression of mir-196b was found specifically in patients with MLL associated leukemias as determined from analysis of 55 primary leukemia samples. Overexpression of mir-196b in bone marrow progenitor cells leads to increased proliferative capacity and survival, as well as a partial block in differentiation. Our results suggest a mechanism whereby increased expression of mir-196b by MLL fusion proteins significantly contributes to leukemia development. (Blood. 2009; 113:3314-3322)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据