Mutant NPM1 Maintains the Leukemic State through HOX Expression.,Cancer Cell

当前位置： X-MOL 学术 › Cancer Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Mutant NPM1 Maintains the Leukemic State through HOX Expression.
Cancer Cell ( IF 48.8 ) Pub Date : 2018-Sep-10 , DOI: 10.1016/j.ccell.2018.08.005
Lorenzo Brunetti ₁ , Michael C Gundry ₂ , Daniele Sorcini ₃ , Anna G Guzman ₄ , Yung-Hsin Huang ₅ , Raghav Ramabadran ₆ , Ilaria Gionfriddo ₃ , Federica Mezzasoma ₃ , Francesca Milano ₃ , Behnam Nabet ₇ , Dennis L Buckley ₈ , Steven M Kornblau ₉ , Charles Y Lin ₁₀ , Paolo Sportoletti ₃ , Maria Paola Martelli ₃ , Brunangelo Falini ₃ , Margaret A Goodell ₁₁

Affiliation

Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, 06132 Perugia, Italy.
Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Centro di Ricerca Emato-Oncologica (CREO), University of Perugia, 06132 Perugia, Italy.
Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Leukemia and Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Stem Cell and Regenerative Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Texas Children's Hospital and Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. Finally, we show that XPO1 inhibition relocalizes NPM1c to the nucleus, promotes differentiation of AML cells, and prolongs survival of Npm1-mutated leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.

中文翻译：

突变 NPM1 通过 HOX 表达维持白血病状态。

NPM1 是细胞遗传学正常的急性髓系白血病 (AML) 中最常见的突变基因。在 AML 细胞中，NPM1 突变导致突变蛋白 (NPM1c) 的细胞质定位异常；然而，尚不清楚 NPM1c 是否需要维持白血病状态。在这里，我们发现，通过核重新定位或靶向降解，NPM1c 从细胞质中丢失，会导致同源框 (HOX) 基因立即下调，然后发生分化。最后，我们发现 XPO1 抑制使 NPM1c 重新定位到细胞核，促进 AML 细胞的分化，并延长 Npm1 突变的白血病小鼠的存活时间。我们描述了 NPM1 突变 AML 细胞对 NPM1c 的精确依赖性，为在 NPM1 突变的 AML 中使用核输出抑制剂提供了理论基础。

更新日期：2018-09-11

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南