PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

Jamrog Laura; Chemin Guillaume; Fregona VincentCoster LuciePasquet MarleneOudinet ChloeRouquie NellyPrade NaisLagarde StephanieCresson CharlotteHebrard SylvieNgoc Sa Nguyen HuuBousquet MarinaQuelen CathyBrousset PierreMancini Stephane J. C.Delabesse EricKhamlichi Ahmed AmineGerby BastienBroccardo Cyril

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PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

机译：PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

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PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human B-ALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in B-ALL development, we generated a knockin mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed B-ALL with an incidence of 80. Leukemic transformation was associated with recurrent secondary mutations on Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN-regulated gene candidates that establish the molecular bases of the preleukemic state to drive B-ALL initiation. Hence, our study provides a new in vivo model of human B-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2018年第41期|10357-10362|共6页
作者
Jamrog Laura; Chemin Guillaume; Fregona VincentCoster LuciePasquet MarleneOudinet ChloeRouquie NellyPrade NaisLagarde StephanieCresson CharlotteHebrard SylvieNgoc Sa Nguyen HuuBousquet MarinaQuelen CathyBrousset PierreMancini Stephane J. C.Delabesse EricKhamlichi Ahmed AmineGerby BastienBroccardo Cyril;
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作者单位

Univ Toulouse, CNRS, UPS, IPBS, F-31077 Toulouse, France;

UPS, CRCT, INSERM, CNRS ERL5294,Lab Excellence Toulouse Canc TOUCAN, F-31037 Toulouse, France;

Aix Marseille Univ, CNRS, INSERM, IPC,CRCM, F-13009 Marseille, FranceUniv Toulouse III Paul Sabatier UPS, INSERM, Univ Toulouse, CRCT, F-31037 Toulouse, FranceCtr Hosp Univ CHU Toulouse, Lab Hematol, F-31000 Toulouse, FranceCHU Toulouse, Dept Pediat Hematol, F-31000 Toulouse, France;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
B-cell acute lymphoblastic leukemia; engineered mouse models; PAX5 fusion proteins; leukemia initiation; oncogenic transformation;

PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

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