A20 deficiency in hematopoietic stem cells causes lymphopenia and myeloproliferation due to elevated Interferon-γ signals

Nakagawa, Masahiro; Rathinam, Chozha Vendan

doi:10.1038/s41598-019-49038-8

Cited by 8 publications

(7 citation statements)

References 40 publications

(66 reference statements)

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“…This hematopoietic phenotype very closely resembles phenotypes observed when a phosphorylationmimic Ikk2 (IKBKB) S177E, S181E was expressed panhematopoietically in mice, either heterozygously (129) or homozygously (130). It also resembles mouse phenotypes obtained when A20/TNFAIP3, an inhibitor of NFkB signaling activation by activated TNFR1, TLRs, and other signaling receptors, was eliminated (131)(132)(133)(134). Furthermore, the .…”

Section: Nfκb Pathway Hyperactivation Is Systemic In Mpns and May Affect Stromal-hematopoietic Interactionssupporting

confidence: 67%

“…HSPC phenotypes were dependent on NFkB hyperactivation in HSPC, as they could be entirely rescued by hematopoietic expression of the nondegradable IkBa S32A, S36A "super repressor" mutant. NFkB hyperactivation in HSPC promoted myeloid differentiation with loss of HSPCs and lymphocytes, resulting in pancytopenia and bone marrow failure (a phenotype also observed to result from pan-hematopoietic NFkB hyperactivation in mice) (129)(130)(131)(132)(133). (B) Bone marrow remodeling by hematopoietic Jak2 V617F, analogous to human MPNs.…”

Section: Nfκb Pathway Hyperactivation Is Systemic In Mpns and May Affect Stromal-hematopoietic Interactionsmentioning

confidence: 99%

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Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms

et al. 2021

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Myeloid neoplasms, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), feature clonal dominance and remodeling of the bone marrow niche in a manner that promotes malignant over non-malignant hematopoiesis. This take-over of hematopoiesis by the malignant clone is hypothesized to include hyperactivation of inflammatory signaling and overproduction of inflammatory cytokines. In the Ph-negative MPNs, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation of polycythemia vera (PV) or essential thrombocythemia (ET) to secondary myelofibrosis (MF), and the equivalent emergence of primary myelofibrosis (PMF). Bone marrow fibrosis itself is thought to be mediated heavily by the cytokine TGF-β, and possibly other cytokines produced as a result of hyperactivated JAK2 kinase in the malignant clone. MF also features extramedullary hematopoiesis and progression to bone marrow failure, both of which may be mediated in part by responses to cytokines. In MF, elevated levels of individual cytokines in plasma are adverse prognostic indicators: elevated IL-8/CXCL8, in particular, predicts risk of transformation of MF to secondary AML (sAML). Tumor necrosis factor (TNF, also known as TNFα), may underlie malignant clonal dominance, based on results from mouse models. Human PV and ET, as well as MF, harbor overproduction of multiple cytokines, above what is observed in normal aging, which can lead to cellular signaling abnormalities separate from those directly mediated by hyperactivated JAK2 or MPL kinases. Evidence that NFκB pathway signaling is frequently hyperactivated in a pan-hematopoietic pattern in MPNs, including in cells outside the malignant clone, emphasizes that MPNs are pan-hematopoietic diseases, which remodel the bone marrow milieu to favor persistence of the malignancy. Clinical evidence that JAK2 inhibition by ruxolitinib in MF neither reliably reduces malignant clonal burden nor eliminates cytokine elevations, suggests targeting cytokine mediated signaling as a therapeutic strategy, which is being pursued in new clinical trials. Greater knowledge of inflammatory pathophysiology in MPNs can therefore contribute to the development of more effective therapy.

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Section: Nfκb Pathway Hyperactivation Is Systemic In Mpns and May Affect Stromal-hematopoietic Interactionssupporting

confidence: 67%

Section: Nfκb Pathway Hyperactivation Is Systemic In Mpns and May Affect Stromal-hematopoietic Interactionsmentioning

confidence: 99%

Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms

et al. 2021

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“…Highlighting the physiological role of A20, various polymorphisms of the A20/TNFAIP3 gene resulting in reduced expression of functional gene product are linked to inflammatory and autoimmune diseases (22,23). With respect to cancers, A20's role remains controversial, because A20 may be oncogenic or tumor suppressive depending on the tissue of origin (24)(25)(26)(27)(28)(29). In this work, we found a function for A20 in NSCLC.…”

Section: Introductionmentioning

confidence: 57%

Down-regulation of A20 promotes immune escape of lung adenocarcinomas

et al. 2021

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Inflammation is a well-known driver of lung tumorigenesis. One strategy by which tumor cells escape tight homeostatic control is by decreasing the expression of the potent anti-inflammatory protein tumor necrosis factor alpha–induced protein 3 (TNFAIP3), also known as A20. We observed that tumor cell intrinsic loss of A20 markedly enhanced lung tumorigenesis and was associated with reduced CD8+ T cell–mediated immune surveillance in patients with lung cancer and in mouse models. In mice, we observed that this effect was completely dependent on increased cellular sensitivity to interferon-γ (IFN-γ) signaling by aberrant activation of TANK-binding kinase 1 (TBK1) and increased downstream expression and activation of signal transducer and activator of transcription 1 (STAT1). Interrupting this autocrine feed forward loop by knocking out IFN-α/β receptor completely restored infiltration of cytotoxic T cells and rescued loss of A20 depending tumorigenesis. Downstream of STAT1, programmed death ligand 1 (PD-L1) was highly expressed in A20 knockout lung tumors. Accordingly, immune checkpoint blockade (ICB) treatment was highly efficient in mice harboring A20-deficient lung tumors. Furthermore, an A20 loss-of-function gene expression signature positively correlated with survival of melanoma patients treated with anti–programmed cell death protein 1. Together, we have identified A20 as a master immune checkpoint regulating the TBK1–STAT1–PD-L1 axis that may be exploited to improve ICB therapy in patients with lung adenocarcinoma.

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“…Consistently, our studies demonstrated that loss of Itch (a member of HECT domain family of E3 ligases) caused abnormal hematopoiesis and defective HSC functions 57 . Recent studies from our lab established that a deficiency of A20 (a ubiquitin editing enzyme) causes severe HSC defects and functions, which ultimately leads to pancytopenia and premature death 37,58,59 . Interestingly, Trim28 protein possesses a RING finger domain and has been identified to exert E3 ubiquitin ligase functions on substrates including p53, AMPK and CDK9 proteins 13,60 .…”

Section: Discussionmentioning

confidence: 99%

Trim28 plays an indispensable role in maintaining functions and transcriptional integrity of hematopoietic stem cells

Silvestri

Rathinam

2022

Preprint

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Hematopoiesis is a complex process that is regulated at multiple levels and through both intrinsic and extrinsic regulators. Trim28 is a multidomain protein that functions as a transcription factor and E3 ubiquitin ligase. Recent studies have established the pivotal roles of Trim28 in a variety of pathophysiologic processes including inflammation, autoimmune disorders, viral pathogenesis, cancer, tumor microenvironment and epithelial-to- mesenchymal transition. However, importance of Trim28 in early hematopoiesis, particularly in the maintenance and functions of hematopoietic stem and progenitor cells (HSPCs), remains largely unknown. In the present study, we identified Trim28 as a critical regulator of self-renewal, quiescence, and functions of hematopoietic stem cells (HSC). Conditional ablation of Trim28 in HSCs leads to perinatal lethality, due to pancytopenia within the hematopoietic lineage. Loss of Trim28 in HSCs affects their differentiation into myeloid-, erythroid-, and lymphoid- lineages. Trim28 deletion leads to altered frequencies and absolute numbers of HSCs, Multipotent Progenitors (MPPs) and lineage committed progenitors in the bone marrow (BM). Primary- and secondary- BM transplantation studies identified an indispensable and a cell-intrinsic role for Trim28 in HSCs. Mechanistic studies identified hyperproliferation of HSPCs and deregulated expression of cell cycle regulators in HSPCs. Strikingly, gene expression studies demonstrated that Trim28 deficiency impairs the transcriptional landscape and transcription factors signatures of HSPCs. In essence, these studies highlight a previously unknown role for Trim28 in the maintenance, functions, and multi-lineage differentiation of HSPCs.

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A20 deficiency in hematopoietic stem cells causes lymphopenia and myeloproliferation due to elevated Interferon-γ signals

Cited by 8 publications

References 40 publications

Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms

Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms

Down-regulation of A20 promotes immune escape of lung adenocarcinomas

Trim28 plays an indispensable role in maintaining functions and transcriptional integrity of hematopoietic stem cells

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