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Roles of GATA-2/retinoic acid receptor pathways and TEL-AML1 translocation in leukemia

GATA-2/视黄酸受体途径和 TEL-AML1 易位在白血病中的作用

基本信息

批准号：
15591037
负责人：
TSUZUKI Shinobu
金额：
$ 2.3万
依托单位：
Aichi Cancer Center
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591037/
关键词：
GATA-2 retinoic acid receptor leukemia TEL-AML1 pro-B cells

项目摘要

(1)Although abnormal retinoic acid receptors are known to cause leukemia, the mechanisms thereby are not clear. We have found retinoic acid receptors are capable of binding to transcription factor GATA-2,and through this interaction GATA-2 functions are rendered responsible to retinoic acid. These findings suggest that retinoic acid exert its action, in addition to canonical receptors, via GATA-2 factor that are normally expressed in immature hematopoietic cells. Indeed, we were able to show that colony formation activities of hematopoietic cells are affected by retinoic acid. Leukemia-associated abnormal retinoic acid receptors may disrupt normal GATA-2 functions, thus leading to leukemia.(2)TEL-AML1 is a fusion gene generated as a result of t(12;21) chromosomal translocation, and the commonest genetic abnormality in child acute lymphocytic leukemia. This translocation is linked to pro-B cell leukemia, but the molecular mechanisms involved are not clear. We have modeled the TEL-AML1 translocation in mice and analyzed its function. The mice were found to have relative accumulation of pro-B cells at the expense of more differentiated stages of B cells, thus providing evidence that TEL-AML1 fusion gene product is capable of inhibiting B cell differentiation program. More detailed analysis is currently conducted.

（1）虽然已知异常的视黄酸受体会引起白血病，但其机制尚不清楚。我们已经发现视黄酸受体能够与转录因子加塔-2结合，并且通过这种相互作用使得加塔-2的功能对视黄酸负责。这些发现表明，视黄酸发挥其作用，除了典型的受体，通过加塔-2因子，通常在未成熟的造血细胞中表达。事实上，我们能够证明造血细胞的集落形成活性受到视黄酸的影响。白血病相关的异常视黄酸受体可能破坏正常的加塔-2功能，从而导致白血病。（2）TEL-AML 1是t（12;21）染色体易位的融合基因，是儿童急性淋巴细胞白血病最常见的遗传异常。这种易位与前B细胞白血病有关，但涉及的分子机制尚不清楚。我们在小鼠中建立了TEL-AML 1易位模型并分析了其功能。发现小鼠以B细胞的更多分化阶段为代价而具有前B细胞的相对积累，从而提供了TEL-AML 1融合基因产物能够抑制B细胞分化程序的证据。目前正在进行更详细的分析。