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- 조회120
Blood, Jun 10 2025, blood.2024028033 | https://doi.org/10.1182/blood.2024028033
An in vivo barcoded CRISPR-Cas9 screen identifies Ncoa4-mediated ferritinophagy as a dependence in Tet2-deficient hematopoiesis
Justin Loke* (1,2), Peter G. Kim* (1), Thuy T. P. Nguyen (3), Meaghan Boileau (4), Marie McConkey (1), Aidan Miller (1), Wesley Shin (1), Christopher B. Hergott (1,5), Maria Ericsson (6), Anja Nordstrom (6), Paula Montero Llopis (7), Scott Armstrong (4), Joseph D. Mancias (3), Benjamin L. Ebert (1,8)
1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2 University of Birmingham, Birmingham, United Kingdom
3 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA
4 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
5 Department of Pathology, Brigham and Women’s Hospital, Boston, MA
6 Department of Cell Biology, Harvard Medical School, Boston, MA
7 MicRoN Core, Harvard Medical School, Boston, MA
8 Broad Institute, Cambridge, MA
Correspondence: Benjamin L. Ebert
*Contributed equally to this paper.
1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2 University of Birmingham, Birmingham, United Kingdom
3 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA
4 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
5 Department of Pathology, Brigham and Women’s Hospital, Boston, MA
6 Department of Cell Biology, Harvard Medical School, Boston, MA
7 MicRoN Core, Harvard Medical School, Boston, MA
8 Broad Institute, Cambridge, MA
Correspondence: Benjamin L. Ebert
*Contributed equally to this paper.
Abstract
TET2 is among the most commonly mutated genes in both clonal hematopoiesis and myeloid malignancies, thus, the ability to identify selective dependencies in TET2 deficient cells has broad translational significance. Here, we identify regulators of Tet2 knockout (KO) hematopoietic stem and progenitor cell (HSPC) expansion using an in vivo CRISPR-Cas9 KO screen, in which nucleotide barcoding enabled large-scale clonal tracing of Tet2 deficient HSPCs in a physiological setting. Our screen identified candidate genes, including Ncoa4, that are selectively required for Tet2 KO clonal outgrowth compared to wild-type (WT). Ncoa4 targets ferritin for lysosomal degradation (ferritinophagy), maintaining intracellular iron homeostasis by releasing labile iron (Fe2+) in response to cellular demands. In Tet2-deficient HSPCs, increased mitochondrial ATP production correlates with increased cellular iron requirements, and in turn, promotes Ncoa4-dependent ferritinophagy. Restricting iron availability reduces Tet2 KO stem cell numbers, revealing a dependency in TET2-mutated myeloid neoplasms.
논문정보
- Research article
- 2025년 06월 (BRIC 등록일 2025-06-11)
- 국외 연구진
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