Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by pro-inflammatory cytokine induced lncRNA Morrbid

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Abstract

Diabetes mellitus (DM) is a risk factor for cancer development. However, the role of DM induced hyperglycemic stress (HG) in the development of blood cancer is poorly understood, largely due to lack of appropriate animal models. Epidemiologic studies show that individuals with DM are more likely to possess higher rate of mutations in genes found in pre-leukemic stem and progenitor cells (pre-LHSC/Ps) including in the epigenetic regulator TET2. TET2-mutant pre-LHSC/Ps require additional hits to evolve into a full-blown leukemia and/or aggressive myeloproliferative neoplasm (MPN). Cell intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the role of extrinsic factors is poorly understood. Utilizing a novel mouse model bearing haploinsufficiency of Tet2, to mimic the human pre-LHSC/P condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces HG and Type-1 DM, we show that the compound mutant mice develop a lethal form of MPN and/or acute myeloid leukemia (AML). RNAseq revealed that this is in part due to upregulation of pro-inflammatory pathways, thereby generating a feedforward loop, including the expression of an anti-apoptotic lncRNA Morrbid. Loss of Morrbid in the compound mutants rescues the lethality and mitigates the development of MPN/AML. Our results describe a novel mouse model for age-dependent AML/MPN and suggest that HG stress acts as an environmental driver for myeloid neoplasm, which could be effectively prevented by reducing the expression of inflammation-related lncRNA Morrbid.

Authors

Zhigang Cai, Xiaoyu Lu, Chi Zhang, Sai Nelanuthala, Fabiola Aguilera, Abigail Hadley, Baskar Ramdas, Fang Fang, Kenneth P. Nephew, Jonathan J. Kotzin, Adam Williams, Jorge Henao-Mejia, Laura S. Haneline, Reuben Kapur

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

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Abstract

Graft-versus-host disease (GVHD) causes failed reconstitution of donor plasmacytoid dendritic cells (pDCs) that are critical for immune protection and tolerance. We used both murine and human systems to uncover the mechanisms whereby GVHD induces donor pDC defects. GVHD depleted Flt3-expressing donor multipotent progenitors (MPPs) that sustained pDCs, leading to impaired generation of pDCs. MPP loss was associated with decreased amounts of MPP-producing hematopoietic stem cells (HSCs) and oxidative stress-induced death of proliferating MPPs. Additionally, alloreactive T cells produced GM-CSF to inhibit MPP expression of Tcf4, the transcription factor essential for pDC development, subverting MPP production of pDCs. GM-CSF did not affect the maturation of pDC precursors. Notably, enhanced recovery of donor pDCs upon adoptive transfer early after allogeneic HSC transplantation repressed GVHD and restored the de novo generation of donor pDCs in recipient mice. pDCs suppressed the proliferation and expansion of activated autologous T cells via a type-I IFN signaling-dependent mechanism. They also produced PD-L1 and LILRB4 to inhibit T cell production of IFN-. We thus demonstrate that GVHD impairs the reconstitution of tolerogenic donor pDCs by depleting DC progenitors rather than by preventing pDC maturation. MPPs are an important target to effectively bolster pDC reconstitution for controlling GVHD.

Authors

Yuanyuan Tian, Lijun Meng, Ying Wang, Bohan Li, Hongshuang Yu, Yan Zhou, Tien Bui, Alicia Li, Ciril Abraham, Yongping Zhang, Jian Wang, Chenchen Zhao, Shin Mineishi, Stefania Gallucci, David Porter, Elizabeth Hexner, Hong Zheng, Yanyun Zhang, Shaoyan Hu, Yi Zhang

Age-related susceptibility to Coronavirus infections: role of impaired and dysregulated host immunity

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Abstract

Human coronaviruses (hCoVs) cause severe respiratory illness in the elderly. Age-related impairments in innate immunity and sub-optimal virus-specific T cell and antibody responses are believed to cause severe disease upon respiratory virus infections. This phenomenon has recently received increased attention, as elderly patients are at substantially elevated risk for severe COVID-19 disease and experience increased rates of mortality following SARS-CoV-2 infection compared to younger populations. However, the basis for age-related fatal pneumonia following pathogenic hCoVs is not well understood. In this review article, we provide an overview of our current understanding of hCoV-induced fatal pneumonia in the elderly. We describe host immune response to hCoV infections derived from studies of young and aged animal models, and discuss the potential role of age-associated increases in sterile inflammation (inflammaging) and virus-induced dysregulated inflammation in causing age-related severe disease. We also highlight the existing gaps in our knowledge about virus replication and host immune responses to hCoV infection in young and aged individuals..

Authors

Rudragouda Channappanavar, Stanley Perlman

CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis

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Abstract

Membrane protrusion and adhesion to the extracellular matrix, which involves the extension of actin filaments and formation of adhesion complexes, are the fundamental processes for cell migration, tumor invasion, and metastasis. How cancer cells efficiently coordinate these processes remains unclear. Here, we showed that membrane-targeted CLIC1 spatiotemporally regulates the formation of cell-matrix adhesions and membrane protrusions through the recruitment of PIP5Ks to the plasma membrane. Comparative proteomics identified CLIC1 upregulated in human hepatocellular carcinoma (HCC) and associated with tumor invasiveness, metastasis, and poor prognosis. In response to migration-related stimuli, CLIC1 recruited PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane, where PIP5Ks generate a PIP2-rich microdomain to induce the formation of integrin-mediated cell-matrix adhesions and the signaling for cytoskeleon extension. CLIC1 silencing inhibited the attachment of tumor cells to culture plates and the adherence and extravasation in the lung alveoli resulting in suppressed lung metastasis in mice. This study reveals an unrecognized mechanism that spatiotemporally coordinates the formation of both lamellipodium/invadopodia and nascent cell-matrix adhesions for directional migration and tumor invasion/metastasis. The unique traits of upregulation and membrane targeting of CLIC1 in cancer cells make it an excellent therapeutic target for tumor metastasis.

Authors

Jei-Ming Peng, Sheng-Hsuan Lin, Ming-Chin Yu, Sen-Yung Hsieh

Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small cell lung cancer

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Abstract

MYC stimulates both metabolism and protein synthesis, but it is unknown how cells coordinate these complementary programs. Previous work reported that in a subset of small cell lung cancer (SCLC) cell lines, MYC activates guanosine triphosphate (GTP) synthesis and results in sensitivity to inhibitors of the GTP synthesis enzyme inosine monophosphate dehydrogenase (IMPDH). Here we demonstrated that primary MYCHigh human SCLC tumors also contain abundant guanosine nucleotides. We also found that elevated MYC in SCLCs with acquired chemoresistance rendered these otherwise recalcitrant tumors dependent on IMPDH. Unexpectedly, our data indicated that IMPDH links the metabolic and protein synthesis outputs of oncogenic MYC. Co-expression analysis placed IMPDH within the MYC-driven ribosome program, and GTP depletion prevented RNA Polymerase I (Pol I) from localizing to ribosomal DNA. Furthermore, the GTPases GPN1 and GPN3 were upregulated by MYC and directed Pol I to ribosomal DNA. Constitutively GTP-bound GPN1/3 mutants mitigated the effect of GTP depletion on Pol I, protecting chemoresistant SCLC cells from IMPDH inhibition. GTP therefore functions as a metabolic gate tethering MYC-dependent ribosome biogenesis to nucleotide sufficiency through GPN1 and GPN3. IMPDH dependence is a targetable vulnerability in chemoresistant, MYCHigh SCLC.

Authors

Fang Huang, Kenneth Huffman, Zixi Wang, Xun Wang, Kailong Li, Feng Cai, Chendong Yang, Ling Cai, Terry S. Shih, Lauren G. Zacharias, Andrew S. Chung, Qian Yang, Milind D. Chalishazar, Abbie S. Ireland, C. Allison Stewart, Kasey R. Cargill, Luc Girard, Yi Liu, Min Ni, Jian Xu, Xudong Wu, Hao Zhu, Benjamin J. Drapkin, Lauren A. Byers, Trudy G. Oliver, Adi Gazdar, John Minna, Ralph DeBerardinis

Lung megakaryocytes are immune modulatory cells

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Abstract

While platelets are the cellular mediators of thrombosis, platelets are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered as bone marrow (BM) resident cells. However, platelet producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared to BM Mks. We therefore sought to define the immune functions of lung Mks. Using single cell RNA-Seq of BM and lung myeloid enriched cells, we found that lung Mks (MkL) had gene expression patterns that are similar to antigen presenting cells (APC). This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment as evidenced by BM Mks having a MkL like phenotype under the influence of pathogen receptor challenge and lung associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in a MHC II dependent manner both in vitro and in vivo. These data indicated that Mks in the lung had key immune regulatory roles dictated in part by the tissue environment.

Authors

Daphne N. Pariser, Zachary T. Hilt, Sara K. Ture, Sara K. Blick-Nitko, Mark R. Looney, Simon J. Cleary, Estheany Roman-Pagan, Jerry Saunders II, Steve N. Georas, Janelle M. Veazey, Ferralita Madere, Laura Tesoro Santos, Allison M. Arne, Nguyen PT Huynh, Alison C. Livada, Selena M. Guerrero-Martin, Claire E. Lyons, Kelly A. Metcalf Pate, Kathleen E. McGrath, James Palis, Craig Morrell

SARS-CoV-2 specific antibody rearrangements in pre-pandemic immune repertoires of risk cohorts and COVID-19 patients

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Abstract

A considerable fraction of B cells recognize SARS-CoV-2 with germline-encoded elements of their B cell receptor resulting in the production of neutralizing and non-neutralizing antibodies. We found that antibody sequences from different discovery cohorts shared biochemical properties and could be retrieved across validation cohorts confirming the stereotyped character of this naive response in COVID-19. While neutralizing antibody sequences were found independently of disease severity in line with serological data, individual non-neutralizing antibody sequences were associated with fatal clinical courses suggesting detrimental effects of these antibodies. We mined 200 immune repertoires of healthy individuals and 500 of patients with blood or solid cancers - all acquired prior to the pandemic - for SARS-CoV-2 antibody sequences. While the largely unmutated B cell rearrangements occurred in a substantial fraction of immune repertoires from young and healthy individuals, these sequences were less likely found in individuals over 60 years of age and in cancer. This reflects B cell repertoire restriction in aging and cancer and may to a certain extent explain the different clinical COVID-19 courses observed in these risk groups. Future studies will have to address if this stereotyped B cell response to SARS-CoV-2 emerging from unmutated antibody rearrangements will create long-lived memory.

Authors

Lisa Paschold, Donjete Simnica, Edith Willscher, Maria J.G.T. Vehreschild, Jochen Dutzmann, Daniel G. Sedding, Christoph Schultheiß, Mascha Binder

Galectin‐7 downregulation in lesional keratinocytes contributes to enhanced IL‐17A signaling and skin pathology in psoriasis

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Abstract

Psoriasis is a chronic inflammatory skin disease characterized by inflammatory cell infiltration, as well as hyperproliferation of keratinocytes in skin lesions, and is considered a metabolic syndrome. We found that the expression of galectin-7 is reduced in the skin lesions of patients with psoriasis. IL-17A and TNF-α, two cytokines intimately involved in the development of psoriatic lesions, suppressed galectin-7 expression in human primary keratinocytes (HEKn cells) and the immortalized human keratinocyte cell line HaCaT. A galectin-7 knockdown in these cells elevated the production of IL-6 and IL-8 and enhanced ERK signaling when the cells were stimulated with IL-17A. Galectin-7 attenuated IL-17A–induced production of inflammatory mediators by keratinocytes via the miR-146a–ERK pathway. Moreover, galectin-7–deficient mice showed enhanced epidermal hyperplasia and skin inflammation in response to intradermal IL-23 injection. We identified fluvastatin as an inducer of galectin-7 expression by connectivity map (cMAP) analysis, confirmed this effect in keratinocytes, and demonstrated that fluvastatin attenuated IL-6 and IL-8 production induced by IL-17A. Thus, we validate a role of galectin-7 in the pathogenesis of psoriasis, in both epidermal hyperplasia and keratinocyte-mediated inflammatory responses, and formulated a rationale for the use of statins in the treatment of psoriasis.

Authors

Hung-Lin Chen, Chia-Hui Lo, Chi-Chun Huang, Meng-Ping Lu, Po-Yuan Hu, Chang-Shan Chen, Di-Yen Chueh, Peilin Chen, Teng-Nan Lin, Yuan-Hsin Lo, Yu-Ping Hsiao, Daniel K. Hsu, Fu-Tong Liu

What are protective antibody responses to pandemic SARS-CoV-2?

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Abstract

Human antibody responses to severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) hold intense interest with research efforts directed at optimizing antibody-based interventions and monitoring immune status. By relating individual variations in antibody response to coronavirus disease 2019 (COVID-19) severity, beneficial antiviral immune responses may be identified in detail. In this issue of the JCI, Secchi and collaborators describe antibody response profiles in 509 COVID-19 patients from Italy during the 2020 pandemic. The research team found that multiple antibody types to multiple SARS-CoV-2 antigens developed over four weeks. Notably, IgG against the spike receptor binding domain (RBD) was predictive of survival and IgA against the viral spike protein (S protein) associated with rapid virologic clearance. These results may help guide selection of convalescent plasma, hyperimmune products, monoclonal antibodies, and vaccine strategies for COVID-19.

Authors

Jeffrey P. Henderson

Identification of human long non-coding RNAs associated with nonalcoholic fatty liver disease and metabolic homeostasis

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Abstract

A growing number of long non-coding RNAs (lncRNAs) have emerged as vital metabolic regulators. However, most human lncRNAs are non-conserved and highly tissue-specific, vastly limiting our ability to identify human lncRNA metabolic regulators (hLMRs). In this study, we establish a pipeline to identify putative hLMRs that are metabolically sensitive, disease-relevant, and population applicable. We first progressively processed multilevel human transcriptome data to select liver lncRNAs that exhibit highly dynamic expression in the general population, show differential expression in a nonalcoholic fatty liver disease (NAFLD) population, and response to dietary intervention in a small NAFLD cohort. We then experimentally demonstrated the responsiveness of selected hepatic lncRNAs to defined metabolic milieus in a liver-specific humanized mouse model. Furthermore, by extracting a concise list of protein-coding genes that are persistently correlated with lncRNAs in general and NAFLD populations, we predicted the specific function for each hLMR. Using gain- and loss-of-function approaches in humanized mice as well as ectopic expression in conventional mice, we validated the regulatory role of one non-conserved hLMR in cholesterol metabolism by coordinating with an RNA-binding protein, PTBP1, to modulate the transcription of cholesterol synthesis genes. Our work overcome the heterogeneity intrinsic to human data to enable the efficient identification and functional definition of disease-relevant human lncRNAs in metabolic homeostasis.

Authors

Xiangbo Ruan, Ping Li, Yonghe Ma, Chengfei Jiang, Yi Chen, Yu Shi, Nikhil Gupta, Fayaz Seifuddin, Mehdi Pirooznia, Yasuyuki Ohnishi, Nao Yoneda, Megumi Nishiwaki, Gabrijela Dumbovic, John L. Rinn, Yuichiro Higuchi, Kenji Kawai, Hiroshi Suemizu, Haiming Cao