Ripk3 signaling regulates HSCs during stress and represses radiation-induced leukemia in mice

Zhang, Lei; Luo, Huacheng; Ni, Hong‐Min; Liu, Shanhui; Xing, H. Rosie; Zhang, Jun; Sellin, Mark; J, Peter Breslin S; Wei, Wei; Denning, Mitchell F.; Small, William; Ding, Wen–Xing; Huang, Suming; Zhang, Jiwang

doi:10.1016/j.stemcr.2022.04.009

Cited by 9 publications

(2 citation statements)

References 51 publications

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“…Although substantial hematopoietic defects were observed in the primary Robo1 Δ/Δ mice, it was still insufficient to enable this transformation. While the process of BM transplantation may confer specific BM niche, leading to reactive pro-inflammatory processes and innate immune responses, acquired genetic mutations, and activation of several cellular pathways, which eventually facilitate this clonal dominance (39). Multiple studies had showed the analogous difference between primary and BM transplantation mice (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS

Jin,

Chen,

Deng

et al. 2023

Sci. Adv.

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Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 ( ROBO1 ) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42 , a member of the Rho–guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1 -deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42 .

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Section: Discussionmentioning

confidence: 99%

ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS

Jin,

Chen,

Deng

et al. 2023

Sci. Adv.

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“… 7 , 8 In addition, there is a rare set of atypical leukemia with different clinical features. 9 There are several treatment options for leukemia patients including radiation, 10 chemotherapy, 11 monoclonal antibodies, 12 and transplantation of hematopoietic stem cells. 13 Once the disease has occurred, several therapeutic procedures are determined based on the morphologic evaluation of blood cells and bone marrow specimens, analysis of cell-surface expression of cytoplasmic markers, identification of chromosomal abnormalities, or screening for molecular/cytogenetic markers.…”

Section: Introductionmentioning

confidence: 99%

Signaling pathways governing the behaviors of leukemia stem cells

Azizidoost¹,

Nasrolahi²,

Sheykhi-Sabzehpoush³

et al. 2024

Genes & Diseases

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ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression

Wu,

Wang,

Chen

et al. 2023

Advanced Science

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A20‐binding inhibitor of NF‐κB activation (ABIN1) is a polyubiquitin‐binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin‐binding site (Abin1Q478H/Q478H) is generated. These mice develop MDS‐like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1Q478H/Q478H mice. Although Abin1Q478H/Q478H cells are sensitive to RIPK1 kinase–RIPK3–MLKL‐dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase‐dead mutation. This indicates that the necroptosis‐independent function of RIPK3 is critical for anemia development in Abin1Q478H/Q478H mice. Notably, Abin1Q478H/Q478H mice exhibit higher levels of type I interferon (IFN‐I) expression in bone marrow cells compared towild‐type mice. Consistently, blocking type I IFN signaling through the co‐deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.

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Ripk3 signaling regulates HSCs during stress and represses radiation-induced leukemia in mice

Cited by 9 publications

References 51 publications

ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS

ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS

Signaling pathways governing the behaviors of leukemia stem cells

ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression

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