Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia-Reference-Cited by-同舟云学术

Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia

Published:2024-08-02 Issue:31 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Sakthivel Dharaniya¹²³^ORCID,Brown-Suedel Alexandra N.¹²,Lopez Karla E.¹²,Salgar Suruchi¹²^ORCID,Coutinho Luiza E.¹²,Keane Francesca¹,Huang Shixia⁴^ORCID,Sherry Kenneth Mc¹^ORCID,Charendoff Chloé I.¹^ORCID,Dunne Kevin P.¹^ORCID,Robichaux Dexter J.¹^ORCID,Vargas-Hernández Alexander¹²^ORCID,Le BaoChau²,Shin Crystal S.⁵,Carisey Alexandre F.⁶^ORCID,Poreba Marcin⁷,Flanagan Jonathan M.¹²^ORCID,Bouchier-Hayes Lisa¹²⁸^ORCID

Affiliation:

1. Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

2. Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA.

3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

4. Advanced Technology Cores, Department of Molecular and Cellular Biology, Huffington Department of Education, Innovation & Technology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

5. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

6. Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

7. Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw 50370, Poland.

8. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage–induced apoptosis is caspase-2 dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c + cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment of the AKT/mTORC1 pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adj3145

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