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ETV6/RUNX1与BCL2的协同作用增强转基因小鼠的免疫球蛋白产生并加速肾小球肾炎。

Cooperation of ETV6/RUNX1 and BCL2 enhances immunoglobulin production and accelerates glomerulonephritis in transgenic mice.

作者信息

Bauer Eva, Schlederer Michaela, Scheicher Ruth, Horvath Jaqueline, Aigner Petra, Schiefer Ana-Iris, Kain Renate, Regele Heinz, Hoermann Gregor, Steiner Günter, Kenner Lukas, Sexl Veronika, Villunger Andreas, Moriggl Richard, Stoiber Dagmar

机构信息

Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.

出版信息

Oncotarget. 2016 Mar 15;7(11):12191-205. doi: 10.18632/oncotarget.7687.

DOI:10.18632/oncotarget.7687
PMID:26919255
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4914278/
Abstract

The t(12;21) translocation generating the ETV6/RUNX1 fusion gene represents the most frequent chromosomal rearrangement in childhood leukemia. Presence of ETV6/RUNX1 alone is usually not sufficient for leukemia onset, and additional genetic alterations have to occur in ETV6/RUNX1-positive cells to cause transformation. We have previously generated an ETV6/RUNX1 transgenic mouse model where the expression of the fusion gene is restricted to CD19-positive B cells. Since BCL2 family members have been proposed to play a role in leukemogenesis, we investigated combined effects of ETV6/RUNX1 with exogenous expression of the antiapoptotic protein BCL2 by crossing ETV6/RUNX1 transgenic animals with Vav-BCL2 transgenic mice. Strikingly, co-expression of ETV6/RUNX1 and BCL2 resulted in significantly shorter disease latency in mice, indicating oncogene cooperativity. This was associated with faster development of follicular B cell lymphoma and exacerbated immune complex glomerulonephritis. ETV6/RUNX1-BCL2 double transgenic animals displayed increased B cell numbers and immunoglobulin titers compared to Vav-BCL2 transgenic mice. This led to pronounced deposition of immune complexes in glomeruli followed by accelerated development of immune complex glomerulonephritis. Thus, our study reveals a previously unrecognized synergism between ETV6/RUNX1 and BCL2 impacting on malignant disease and autoimmunity.

摘要

产生ETV6/RUNX1融合基因的t(12;21)易位是儿童白血病中最常见的染色体重排。单独存在ETV6/RUNX1通常不足以引发白血病，ETV6/RUNX1阳性细胞还必须发生其他基因改变才能导致转化。我们之前构建了一个ETV6/RUNX1转基因小鼠模型，其中融合基因的表达仅限于CD19阳性B细胞。由于有人提出BCL2家族成员在白血病发生中起作用，我们通过将ETV6/RUNX1转基因动物与Vav-BCL2转基因小鼠杂交，研究了ETV6/RUNX1与抗凋亡蛋白BCL2的外源性表达的联合作用。令人惊讶的是，ETV6/RUNX1和BCL2的共表达导致小鼠疾病潜伏期显著缩短，表明癌基因协同作用。这与滤泡性B细胞淋巴瘤的更快发展和免疫复合物性肾小球肾炎的加重有关。与Vav-BCL2转基因小鼠相比，ETV6/RUNX1-BCL2双转基因动物的B细胞数量和免疫球蛋白滴度增加。这导致肾小球中免疫复合物的明显沉积，随后免疫复合物性肾小球肾炎加速发展。因此，我们的研究揭示了ETV6/RUNX1和BCL2之间以前未被认识到的协同作用，这种协同作用影响恶性疾病和自身免疫。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/d599c5b0d588/oncotarget-07-12191-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/bf641f26795d/oncotarget-07-12191-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/4e0e12414b3b/oncotarget-07-12191-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/ad95c3b3836c/oncotarget-07-12191-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/c3cf20cd43cc/oncotarget-07-12191-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/d599c5b0d588/oncotarget-07-12191-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/bf641f26795d/oncotarget-07-12191-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/4e0e12414b3b/oncotarget-07-12191-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/ad95c3b3836c/oncotarget-07-12191-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/c3cf20cd43cc/oncotarget-07-12191-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/16ac/4914278/d599c5b0d588/oncotarget-07-12191-g005.jpg

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