急性髓系白血病的分子调控:Hoxa9/Meis1-miR-146a
  • 转录因子Meis1在Hox基因过表达的前提下,驱动髓系白血病的发生;
  • 泛(磷酸化)蛋白质组学分析提示:Meis1促进Syk的蛋白表达与活性,Meis1依赖性反馈环上调Syk,剖析此环,Syk成为miR-146a的直接靶点,通过转录因子PU.1,Meis1间接调控其表达;
  • Hoxa9过表达前提下,Syk信号诱导Meis1,概括了Hoxa9/Meis1驱动的白血病的几个白血病形成特征;
  • 抑制Syk则破坏该调控环,延长Hoxa9/Meis1驱动的白血病小鼠的生存期。
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Cancer Cell [IF:26.602]

Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia

Hoxa9和Meis1通过抑制miR-146a协同诱导急性髓系白血病依赖于Syk信号传导通路

10.1016/j.ccell.2017.03.001

2017-04-10, Article

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The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.

First Authors:
Sebastian Mohr,Carmen Doebele,Federico Comoglio,Tobias Berg

Correspondence Authors:
Thomas Oellerich

All Authors:
Sebastian Mohr,Carmen Doebele,Federico Comoglio,Tobias Berg,Julia Beck,Hanibal Bohnenberger,Gabriela Alexe,Jasmin Corso,Philipp Ströbel,Astrid Wachter,Tim Beissbarth,Frank Schnütgen,Anjali Cremer,Nadine Haetscher,Stefanie Göllner,Arefeh Rouhi,Lars Palmqvist,Michael A Rieger,Timm Schroeder,Halvard Bönig,Carsten Müller-Tidow,Florian Kuchenbauer,Ekkehard Schütz,Anthony R Green,Henning Urlaub,Kimberly Stegmaier,R Keith Humphries,Hubert Serve,Thomas Oellerich

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