TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia

被引：131

作者：

Zhang, Haojian ^{[1
]}

Kozono, David E. ^{[1
]}

O'Connor, Kevin W. ^{[1
]}

Vidal-Cardenas, Sofia ^{[1
]}

Rousseau, Alix ^{[2
]}

Hamilton, Abigail ^{[1
]}

Moreau, Lisa ^{[1
]}

Gaudiano, Emily F. ^{[1
]}

Greenberger, Joel ^{[3
]}

Bagby, Grover ^{[4
]}

Soulier, Jean ^{[2
]}

Grompe, Markus ^{[4
]}

Parmar, Kalindi ^{[1
]}

D'Andrea, Alan D. ^{[1
]}

机构：

[1] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA

[2] Univ Paris Diderot, Inst Hematol IUH, F-75010 Paris, France

[3] Univ Pittsburgh, Med Ctr, Dept Radiat Oncol, Pittsburgh, PA 15213 USA

[4] Oregon Hlth & Sci Univ, Portland, OR 97239 USA

来源：

CELL STEM CELL | 2016年 / 18卷 / 05期

关键词：

DNA-DAMAGE RESPONSE; HOMOLOGOUS RECOMBINATION; REPAIR; PATHWAY; MICE; GROWTH; ABNORMALITIES; FANCD2; RAD51; TRANSCRIPTION;

D O I：

10.1016/j.stem.2016.03.002

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Fanconi anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-beta (TGF-beta) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-beta pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived fromFA mice and FA patients. Inhibition of TGF-beta signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-beta signaling contributes to BMF in FA by impairing HSPC function and may be a potential therapeutic target for the treatment of FA.

引用

页码：668 / 681

页数：14

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