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

(1)虽然维甲酸受体异常可导致白血病，但其机制尚不清楚。我们已经发现维甲酸受体能够与转录因子GATA-2结合，通过这种相互作用，GATA-2的功能被维甲酸负责。这些发现表明，除了典型的受体外，维甲酸还通过GATA-2因子发挥作用，而GATA-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动受到维甲酸的影响。白血病相关的视黄酸受体异常可能会扰乱正常的GATA-2功能，从而导致白血病。(2)TEL-AML1是t(12；21)染色体易位产生的融合基因，是儿童急性淋巴细胞白血病中最常见的遗传异常。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。我们在小鼠体内建立了TEL-AML1易位的模型，并对其功能进行了分析。结果发现，TELL-AML1融合基因产物具有抑制B细胞分化的能力，并以B细胞的多分化阶段为代价而相对积聚B细胞。目前正在进行更详细的分析。

(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.