Elevated leukocyte cell numbers (leukocytosis), and monocytes in particular, promote atherosclerosis; however, how they become increased is poorly understood. Mice deficient in the adenosine triphosphate-binding cassette (ABC) transporters ABCA1 and ABCG1, which promote cholesterol efflux from macrophages and suppress atherosclerosis in hypercholesterolemic mice, displayed leukocytosis, a transplantable myeloproliferative disorder, and a dramatic expansion of the stem and progenitor cell population containing Lin − Sca-1 + Kit + (LSK) in the bone marrow.

Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation. (Blood. 2011;117(19):5057-5066) IntroductionHematopoietic stem cells (HSCs) can self-renew and differentiate into all cell types of the hematopoietic system and are regulated by interacting intrinsic and extrinsic mechanisms. 1 Among intrinsic mechanisms, several transcriptional regulators involved as partners of leukemogenic fusion proteins, such as Mll 2-4 and Evi1, 5 are required for normal HSC function, whereas others, such as Runx1 6,7 and Scl,8,9 are essential for the establishment of HSCs during development. PR domain-containing 16 (PRDM16), a 140-kDa zinc finger protein, was originally discovered as a fusion partner in t(1:3)(p36;q21) translocations in acute myeloblastic leukemia (AML) 10,11 and later in t(1;21)(p36;q22) translocations fused to RUNX1. 12,13 In addition, elevated PRDM16 expression, because of promoter hypomethylation, is frequently observed in karyotypically normal AML. 14 Deletion of the PR domain, which shows homology with a SET chromatin remodeling domain and is also present in EVI1, 10 appears important for the leukemogenic properties of human PRDM16. Translocations involving PRDM16 invariably delete the PR domain, 10-13 whereas PR-deleted Prdm16 causes AML in p53 Ϫ/Ϫ mice. 14 Furthermore, both Prdm16 and Evi1 are frequent targets of insertional mutagenesis in mice, causing deletion of the PR domain. 15 Overexpression of Prdm16 expands HSCs in vitro. However, these expanded HSCs cause a myeloproliferative disease after transplantation. 16 Prdm16 has also been shown to be critical for the development of brown adipose tissue in the mouse. PRDM16 is a transcriptional cofactor and interacts with the ligand-activated transcription factor peroxisome proliferatoractivated receptor-␥ and with CCAAT/enhancer-binding protein-␤. 17,18 Although its involvement in leukemic transloc...

Spread of biological species from primary into novel habitats leads to within-species adaptive niche differentiation and is commonly driven by acquisition of point mutations in individual genes that increase fitness in the alternative environment. However, finding footprints of adaptive niche differentiation in specific genes remains a challenge. Here we describe a novel method to analyze the footprint of pathogenicity-adaptive, or pathoadaptive, mutations in the Escherichia coli gene encoding FimH-the major, mannose-sensitive adhesin. Analysis of distribution of mutations across the nodes and branches of the FimH phylogenetic network shows (1) zonal separation of evolutionary primary structural variants of FimH and recently derived ones, (2) dramatic differences in the ratio of synonymous and nonsynonymous changes between nodes from different zones, (3) evidence for replacement hot-spots in the FimH protein, (4) differential zonal distribution of FimH variants from commensal and uropathogenic E. coli, and (5) pathoadaptive functional changes in FimH brought by the mutations. The selective footprint in fimH indicates that the pathoadaptive niche differentiation of E. coli is either in its initial stages or undergoing an evolutionary "source/sink" dynamic.

Summary Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.

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Colorful clones in the blood Stem cells in regenerating tissues such as the blood can acquire mutations that enable a growth advantage, increasing the chance of developing cancer. It is unclear how such diverse mutations promote clonal fitness. Avagyan et al . generated a platform in zebrafish to label clones with unique hues while inducing mutations in genes implicated in human blood disorders. Mutations in some genes caused clones to expand over time, resulting in clonal dominance. Progenitors in the dominant clone expressed anti-inflammatory factors to resist the inflammatory environment produced by their own mature progeny, leading to a self-perpetuating cycle promoting clonal fitness. Targeting these resistance pathways may be used to abate clonal hematopoiesis and prevent its associated pathology. —BAP

One aspect of the multifaceted proposal by A. G. Cairns-Smith, that imperfect crystals have the capacity to act as primitive genes by transferring the disposition of their imperfections from one crystal to another, is investigated. Rather than examining clay minerals, the most likely crystalline genes in the theories of Cairns-Smith, an experiment was designed in a model crystalline system unrelated to the composition of the prebiotic earth but suited to a well-defined test. Plates of potassium hydrogen phthalate riddled with dislocations were studied in order to ascertain whether, according to Cairns-Smith, parallel screw dislocations could serve as an information store with cores akin to punches in an old computer card. Evidence of screw dislocations was obtained from their associated growth hillocks through differential interference contrast microscopy, atomic force microscopy, and luminescence labeling of hillocks in conjunction with confocal laser scanning microscopy. The dispositions of growth active hillocks were quantified by fractal analysis. 'Mother' crystals were cleaved and inheritance was evaluated by the corresponding patterns of luminescence developed in their 'daughters' after continued growth in the presence of fluorophores. Luminescence microscopy proves to be a versatile tool for studying the dynamics of growth active hillocks. In the aggregate, this work speaks to the need for molecular mechanisms of dislocation nucleation.

Hematopoietic stem cells (HSCs) give rise to all differentiated blood cells. Understanding the mechanisms that regulate self-renewal and lineage specification of HSCs is key for developing treatments for many human diseases. Zebrafish have emerged as an excellent model for studying vertebrate hematopoiesis. This review will highlight the unique strengths of zebrafish and important findings that have emerged from studies of blood development and disorders using this system. We discuss recent advances in our understanding of hematopoiesis, including the origin of HSCs, molecular control of their development, and key signaling pathways involved in their regulation. We highlight significant findings from zebrafish models of blood disorders, and discuss their application for investigating stem cell dysfunction in disease and for developing new therapeutics.