Mutant NPM1 Maintains the Leukemic State through HOX Expression

被引：250

作者：

Brunetti, Lorenzo ^{[1
,2
,3
,4
]}

Gundry, Michael C. ^{[1
,2
,3
,5
]}

Sorcini, Daniele ^{[4
]}

Guzman, Anna G. ^{[1
,2
,3
]}

Huang, Yung-Hsin ^{[1
,2
,3
,6
]}

Ramabadran, Raghav ^{[1
,7
]}

Gionfriddo, Ilaria ^{[4
]}

Mezzasoma, Federica ^{[4
]}

Milano, Francesca ^{[4
]}

Nabet, Behnam ^{[10
,11
]}

Buckley, Dennis L. ^{[12
]}

Kornblau, Steven M. ^{[8
,9
]}

Lin, Charles Y. ^{[5
]}

Sportoletti, Paolo ^{[4
]}

Martelli, Maria Paola ^{[4
]}

Falini, Brunangelo ^{[4
]}

Goodell, Margaret A. ^{[1
,2
,3
,5
,7
,10
]}

机构：

[1] Baylor Coll Med, Stem Cell & Regenerat Med, Houston, TX 77030 USA

[2] Texas Childrens Hosp, Ctr Cell & Gene Therapy, Houston, TX 77030 USA

[3] Houston Methodist Hosp, Baylor Coll Med, Houston, TX 77030 USA

[4] Univ Perugia, Ctr Ric Ematooncol CREO, I-06132 Perugia, Italy

[5] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[6] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA

[7] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[8] MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[9] MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA

[10] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[11] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA

[12] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

来源：

CANCER CELL | 2018年 / 34卷 / 03期

基金：

欧洲研究理事会;

关键词：

ACUTE MYELOID-LEUKEMIA; NUCLEAR EXPORT SIGNALS; NUCLEOPHOSMIN NPMC(+) AML; EMBRYONIC STEM-CELL; CYTOPLASMIC NUCLEOPHOSMIN; HEMATOPOIETIC PROGENITORS; TRANSCRIPTION FACTORS; PRECLINICAL ACTIVITY; MOLECULAR SYNERGY; CHIP-SEQ;

D O I：

10.1016/j.ccell.2018.08.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 down-regulation 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.

引用

页码：499 / +

页数：23

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