Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice

Xin, Junping; Breslin, Peter; Wei, Wei; Li, Jing; Gutiérrez, Rafael; Cannova, Joseph; Ni, Allen; Ng, Grace Hwee Boon; Schmidt, Rachel; Chen, Haiyan; Parini, Vamsi; Kuo, Paul C.; Kini, Ameet R.; Stiff, Patrick J.; Zhu, Jiang; Zhang, Jiwang

doi:10.3324/haematol.2016.151514

Cited by 15 publications

(33 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MAP3K7 encodes a kinase that mediates tumor necrosis factor κ (TNFκ), interleukin-1 β (IL-1β), and Toll-like receptor signaling through the NF-κB, JNK, and MAPK pathways. The effects of MAP3K7 loss have been extensively studied and can result in loss or promotion of inflammation depending on cellular context (Ajibade et al, 2012; Lamothe et al, 2012; Sato et al, 2005; Tang et al, 2008; Vink et al, 2013; Xin et al, 2017). Here, we observed that SF3B1 K700E human myeloid or lymphoid leukemia cells stimulated with LPS had enhanced NF-κB activation compared with SF3B1 WT controls (Figures 6D, 6E, S6D, and S6E).…”

Section: Resultsmentioning

confidence: 99%

“…For example, in vivo knockdown of Map3k7 resulted in splenomegaly, myeloproliferation, and extramedullary hematopoiesis, as well as increased immune activation that was exacerbated by LPS (Vink et al, 2013). Similarly, myeloid-specific deletion of Map3k7 heightened the response to inflammatory stimuli and causes a clonal myeloid leukemia (Ajibade et al, 2012; Eftychi et al, 2012; Lamothe et al, 2012; Xin et al, 2017). Interestingly, the pro-inflammatory and leukemogenic effects of Map3k7 loss appear to be restricted to myeloid lineages (Ajibade et al, 2012), in stark contrast to pan-hematopoietic deletion of Map3k7 , which results in complete failure of hematopoiesis (Tang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

et al. 2018

View full text Add to dashboard Cite

Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor κB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

et al. 2018

View full text Add to dashboard Cite

show abstract

“…As discussed above this is illustrated in a model where TNF and IFNγ exhibited opposing functions in acquired aplastic anemia, a condition defined by a loss of functional stem cell units unable to maintain relevant levels of mature blood cells. Here, IFNγ repressed BM hematopoiesis in the wake of an autoimmune response, whereas TNF improved the BMF by blocking type-1 T lymphocyte responses and maintaining the function of myeloid-derived suppressor cells [105].…”

Section: Necroinflammation and Bmfmentioning

confidence: 99%

Necroinflammation emerges as a key regulator of hematopoiesis in health and disease

Jost

Höckendorf

2018

Cell Death Differ

View full text Add to dashboard Cite

The hematopoietic system represents an organ system with an exceptional capacity for the production of mature blood cells from a small and mostly quiescent pool of hematopoietic stem cells (HSCs). This extraordinary capacity includes selfrenewal but also the propensity to rapidly respond to extrinsic needs, such as acute infections, severe inflammation, and wound healing. In recent years, it became clear that inflammatory signals such as cytokines, chemokine and danger signals from pathogens (PAMPs) or dying cells (DAMPs) impact on HSCs, shaping their proliferation status, lineage bias, and repopulating ability and subsequently increasing the output of mature effector cells. However, inflammatory danger signals negatively impact on the capacity of HSCs to self-renew and to maintain their stem cell capabilities. This is evidenced in conditions of chronic inflammation where bone marrow failure may originate from HSC exhaustion. Even in hematopoietic cancers, inflammatory signals shape the phenotype of the malignant clone as exemplified by necrosome-dependent inflammation elicited during malignant transformation in acute myeloid leukemia. Accordingly, understanding the contribution of inflammatory signals, and specifically necroinflammation, to HSC integrity, HSC long-term functionality, and malignant transformation has attracted substantial research and clinical interest. In this review, we highlight recent developments and open questions at the interplay between inflammation, regulated necrosis, and HSC biology in the context of blood cell development, acute and chronic inflammation, and hematopoietic cancer.

show abstract

“…We found that necroptosis of a small portion of stem cell/ progenitors with gene mutation resulted in autoimmune responses, which caused a rapid depletion of bone marrow cells, which could be prevented by blocking necroptotic pathway via deletion of rip3. [35] We speculate that similar roles of necroptosis may also exist in ALS: a small portion MN that die of necroptosis may cause the autoimmune responses, in which the MN-specific antigens are released and presented to CD4 + T cells. These T cells may preferentially develop into pro-inflammatory subsets and further amplify the inflammation/immune responses, and cause more MN death.…”

Section: Necroptosis and Its Implications In Alsmentioning

confidence: 99%

How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

Liu¹,

Zheng²,

Xin³

et al. 2017

View full text Add to dashboard Cite

How to cite this article: Liu JF, Zheng OX, Xin JG, Chen HH, Xin JJ. How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis ? Neuroimmunol Neuroinflammation 2017;4:109-16. Abnormal immune response/inflammation is present in patients of amyotrophic lateral sclerosis (ALS). Autoimmune-related inflammation has been thought to be involved in the pathogenesis of ALS. However, how the abnormal immune responses are initiated, what specific immune cells and how these immune cells are involved in this disease have not been well understood. This is partly owing to two facts of ALS: late diagnosis and chronic nature. The late diagnosis makes it difficult to conclude whether the abnormal immune responses/inflammation is the cause or result of the disease. The chronic nature makes it difficult to determine the best timing for the detection of such autoimmune responses. To resolve these two challenges for research, the authors introduced motor nerve injury (facial nerve axotomy, FNA) into a pre-symptomatic mouse ALS model (8-week-old SOD1 G93A mice), which induces a readily detectable immune response in a predictable time period (3-14 days). The authors found that pre-symptomatic SOD1 G93A mice showed a higher basal level of T cell activation and Th17 cells than WT mice, which can be further increased by FNA. However, why these pro-inflammatory Th lymphocyte MinireviewThis is an open access article distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

show abstract

Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice

Cited by 15 publications

References 56 publications

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

Necroinflammation emerges as a key regulator of hematopoiesis in health and disease

How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

Contact Info

Product

Resources

About