PAX5-ETV6癌蛋白在促进B细胞急性淋巴细胞白血病中的分子作用。
Molecular role of the PAX5-ETV6 oncoprotein in promoting B-cell acute lymphoblastic leukemia.
作者信息
Smeenk Leonie, Fischer Maria, Jurado Sabine, Jaritz Markus, Azaryan Anna, Werner Barbara, Roth Mareike, Zuber Johannes, Stanulla Martin, den Boer Monique L, Mullighan Charles G, Strehl Sabine, Busslinger Meinrad
机构信息
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
出版信息
EMBO J. 2017 Mar 15;36(6):718-735. doi: 10.15252/embj.201695495. Epub 2017 Feb 20.
PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here, we studied the function of PAX5-ETV6 and PAX5-FOXP1 in mice expressing these proteins from the locus. Both proteins arrested B-lymphopoiesis at the pro-B to pre-B-cell transition and, contrary to their proposed dominant-negative role, did not interfere with the expression of most regulated Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressors in promoting B-ALL development. Regulated Pax5-Etv6 target genes identified in these B-ALLs encode proteins implicated in pre-B-cell receptor (BCR) signaling and migration/adhesion, which could contribute to the proliferation, survival, and tissue infiltration of leukemic B cells. Together with similar observations made in human PAX5-ETV6 B-ALLs, these data identified PAX5-ETV6 as a potent oncoprotein that drives B-cell leukemia development.
PAX5在B淋巴细胞白血病（B-ALL）中是一种肿瘤抑制因子，而PAX5融合蛋白在B-ALL发展中的作用在很大程度上尚不清楚。在此，我们研究了在小鼠中从该基因座表达这些蛋白的PAX5-ETV6和PAX5-FOXP1的功能。这两种蛋白均在B淋巴细胞生成过程中使前B细胞向pre-B细胞的转变停滞，并且与它们所提出的显性负性作用相反，并未干扰大多数受调控的Pax5靶基因的表达。Pax5-Etv6（而非Pax5-Foxp1）与细胞周期蛋白依赖性激酶抑制因子2a/2b（Cdkna2a/b）肿瘤抑制因子的缺失协同作用，促进B-ALL的发展。在这些B-ALL中鉴定出的受调控的Pax5-Etv6靶基因编码与pre-B细胞受体（BCR）信号传导以及迁移/黏附相关的蛋白，这可能有助于白血病B细胞的增殖、存活和组织浸润。连同在人类PAX5-ETV6 B-ALL中所做的类似观察结果，这些数据确定PAX5-ETV6是一种驱动B细胞白血病发展的强效癌蛋白。
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