Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies1–7. In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage1,4,8,9. However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2−/− mice8,9 and humans with TET2 mutations1,3,5–7, suggesting that extrinsic non-cell-autonomous factors are required for disease onset. Here we show that bacterial translocation and increased interleukin-6 production, resulting from dysfunction of the small-intestinal barrier, are critical for the development of PMP in mice that lack Tet2 expression in haematopoietic cells. Furthermore, in symptom-free Tet2−/− mice, PMP can be induced by disrupting intestinal barrier integrity, or in response to systemic bacterial stimuli such as the toll-like receptor 2 agonist. PMP was reversed by antibiotic treatment and failed to develop in germ-free Tet2−/− mice, which illustrates the importance of microbial signals in the development of this condition. Our findings demonstrate the requirement for microbial-dependent inflammation in the development of PMP and provide a mechanistic basis for the variation in PMP penetrance observed in Tet2−/− mice. This study will prompt new lines of investigation that may profoundly affect the prevention and management of haematopoietic malignancies.
Age-associated clonal hematopoiesis caused by acquired mutations in myeloid cancer-associated genes is highly prevalent in the normal population. Its etiology, biological impact on hematopoiesis, and oncogenic risk is poorly defined at this time. To gain insight into this phenomenon, we analyzed a cohort of 2530 related and unrelated hematologically normal individuals (ages 55 to 101 years). We used a sensitive gene-targeted deep sequencing approach to gain precision on the exact prevalence of driver mutations and the proportions of affected genes. Mutational status was correlated with biological parameters. We report a higher overall prevalence of driver mutations (13.7%), which occurred mostly (93%) in or and were highly age-correlated. Mutation in these 2 genes had some distinctive effects on end points. mutations were more age-dependent, associated with a modest neutropenic effect (9%, = .012), demonstrated familial aggregation, and associated with chronic obstructive pulmonary disease. Mutations in had no impact on blood counts or indices. Mutational burden of both genes correlated with X-inactivation skewing but no significant association with age-adjusted telomere length reduction was documented. The discordance between the high prevalence of mutations in these 2 genes and their limited biological impact raise the question of the potential role of dysregulated epigenetic modifiers in normal aging hematopoiesis, which may include support to failing hematopoiesis.
Key Points• Quantitative proteomics identifies BRG as the main ATPase of BAF complexes expressed in leukemia.• BRG is essential for the proliferation of leukemic cells.In mammals, combinatorial assembly of alternative families of subunits confers functional specificity to adenosine triphosphate (ATP)-dependent SWI/SNF-like Brg/Brmassociated factor (BAF) chromatin remodeling complexes by creating distinct polymorphic surfaces for interaction with regulatory elements and DNA-binding factors.Although redundant in terms of biochemical activity, the core ATPase subunits, BRG/ SMARCA4 and BRM/SMARCA2, are functionally distinct and may contribute to complex specificity. Here we show using quantitative proteomics that BAF complexes expressed in leukemia are specifically assembled around the BRG ATPase. Moreover, using a mouse model of acute myeloid leukemia, we demonstrate that BRG is essential for leukemia maintenance, as leukemic cells lacking BRG rapidly undergo cell-cycle arrest and apoptosis. Most importantly, we show that BRG is dispensable for the maintenance of immunophenotypic long-term repopulating hematopoietic stem cells, suggesting that adroit targeting of BRG in leukemia may have potent and specific therapeutic effects. (Blood. 2014;123(11):1720-1728
In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.
We analyzed DNA from polymorphonuclear (PMN) cells, monocytes, B cells, and T cells of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Three lineage categories were defined: myeloid (PMN with or without monocytes), myelolympho-B (myeloid and B cells), and multipotent (myeloid, B and T cells). Six individuals with aberrant patterns were excluded from analysis. Ninety-four had a single mutation (56 in , 24 in, 7 in other genes [, , or ]). Fourteen had multiple mutations. The lineage restriction patterns of single- or -mutated individuals were different. The proportion of myeloid restricted mutations was higher for (54.2%, 13 of 24) than for (23.2%, 13 of 56) ( < .05). It was similar for myelolympho-B category but with a 1.5 fold greater proportion of myeloid cells for individuals ( < .05). Importantly, 0% (0 of 24) of the individuals with mutation in the multipotent category in contrast to 35.7% (20 of 56) for ( < .01). The clone size predicted multipotent pattern for suggesting a time delay for extensive lineage clonal dominance. These distinctive features may be important in deciphering the transformation mechanisms of these frequent mutations.
In both invertebrates and vertebrates, transcriptional co-repressors of the Groucho/transducin-like Enhancer of split (Gro/ TLE) family regulate a number of developmental mechanisms, including neuronal differentiation. The pleiotropic activity of Gro/TLE depends on context-specific interactions with a variety of DNA-binding proteins. Most of those factors engage Gro/ TLE through two different types of short peptide motifs, the WRP(W/Y) tetrapeptide and the Engrailed homology 1 (Eh1) sequence (FXIXXIL). The aim of this study was to elucidate the contribution of WRP(W/Y) and Eh1 motifs to mammalian Gro/ TLE anti-neurogenic activity. Here we describe point mutations within the C-terminal WD40 repeat domain of Gro/TLE1 that do not perturb protein folding but disrupt the ability of Gro/ TLE1 to inhibit the differentiation of cerebral cortex neural progenitor cells into neurons. One of those mutations, L743F, selectively blocks binding to Hes1, an anti-neurogenic basic helix-loop-helix protein that harbors a WRPW motif. In contrast, the L743F mutation does not disrupt binding to Engrailed1 and FoxG1, which both contain Eh1 motifs, nor to Tcf3, which binds to the Gro/TLE N terminus. These results demonstrate that the recruitment of transcription factors harboring WRP(W/Y) tetrapeptides is essential to the antineurogenic function of Gro/TLE1.Transcriptional co-repressors of the Groucho/transducinlike Enhancer of split (Gro/TLE) 3 family play critical roles during multiple developmental processes, including neuronal differentiation in the developing mammalian forebrain (1). Gro/ TLEs act as co-repressors for a variety of DNA-binding transcription factors. Some of those proteins are dedicated transcriptional repressors while others mediate repression or transactivation depending on specific contexts (1-4). Through interactions with a large number of transcriptional regulators, Gro/ TLEs are involved in the gene regulatory functions of a variety of signaling pathways, including Notch, Wnt/Wingless, transforming growth factor- superfamily, and epidermal growth factor receptor signal transduction mechanisms (1-6). Moreover, growing evidence suggests important roles for Gro/TLEs in integrating these different signaling cascades during several developmental processes (1, 5).The regulation of neuronal differentiation was one of the first functions of Gro/TLE proteins to be characterized. During Drosophila neural development, Gro participates in the Notch-mediated lateral inhibition mechanism that restricts the number of committed neuroblasts within proneural clusters containing initially equipotential presumptive neural progenitor cells (7,8). Neuroblasts undergoing commitment activate the Notch receptor in adjacent cells, resulting in the transcriptional induction of genes encoding basic helix loop helix (bHLH) proteins of the Hairy/Enhancer of split (Hes) family. These DNA-binding proteins recruit Gro to form complexes that repress the expression, as well as biochemical activity, of proteins that promote neuronal differentia...
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