Broad maternal geographic origin of domestic sheep in Anatolia and the Zagros.

We investigated the controversial origin of domestic sheep (Ovis aries) using large samples of contemporary and ancient domestic individuals and their closest wild relatives: the Asiatic mouflon (Ovis gmelini), the urial (Ovis vignei) and the argali (Ovis ammon). A phylogeny based on mitochondrial DNA, including 213 new cytochrome-b sequences of wild Ovism confirmed that O. gmelini is the maternal ancestor of sheep and precluded mtDNA contributions from O. vignei (and O. gmelini × O. vignei hybrids) to domestic lineages. We also produced 54 new control region sequences showing shared haplogroups (A, B, C and E) between domestic sheep and wild O. gmelini which localized the domestication center in eastern Anatolia and central Zagros, excluding regions further east where exclusively wild haplogroups were found. This overlaps with the geographic distribution of O. gmelini gmelini, further suggesting that the maternal origin of domestic sheep derives from this subspecies. Additionally, we produced 57 new CR sequences of Neolithic sheep remains from a large area covering Anatolia to Europe, showing the early presence of at least three mitochondrial haplogroups (A, B and D) in Western colonization routes. This confirmed that sheep domestication was a large-scale process that captured diverse maternal lineages (haplogroups).

RAF inhibitors that evade paradoxical MAPK pathway activation.

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.

Unilateral lag screw fixation of isolated non-union atlas lateral mass fracture: a new technical note.

We describe a novel and new technique of posterior unilateral lag screw fixation of non-union atlas lateral mass fracture. A 46-year-old man presented with cervical pain and tenderness after a vehicle turn over accident and he was diagnosed to have left atlas lateral mass fracture. He was initially treated by immobilization using Minerva orthosis. About 2 months later, he developed severe neck pain and limitation of motion and thus he was scheduled for operation due to non-union atlas lateral mass fracture. A 28 mm lag screw was inserted under anterior-posterior and lateral fluoroscopic views. The entrance point was at the dorsal aspect of left atlas posterior arc at its junction to the lateral mass, and by using the trajectory of 10 degrees medial and 22 degrees cephalad fracture reduction was achieved. Unilateral lag screw fixation of atlas fractures is an appropriate, safe and effective surgical technique for the management of unilateral atlas fractures.

Anterior screw fixation in type II odontoid fracture in an 18-month-old girl: a case report and review of the literature.

Odontoid fractures are among the rare cervical spine injuries in pediatric population and thus the optimal management of these injuries is controversial. The increasing trend in road traffic accidents and improvement in diagnostic modalities has led to an increased detection of odontoid fractures in pediatric population. We herein report type II odontoid fracture in an 18-month-old girl after falling off the motorcycle leading to hyperextension and flexion injury. She was successfully treated with anterior odontoid screw fixation followed by immobilization with hard collar for 2 months. Callus formation was detected after 6 weeks and complete remodeling was observed at 6-year follow-up visit. This girl is among the youngest patients with type II odontoid fracture reported in literature being treated with anterior screw fixation. Further clinical series are needed to provide evidence for optimal management of odontoid fractures.

Whole mitochondrial genomes unveil the impact of domestication on goat matrilineal variability.

BACKGROUND: The current extensive use of the domestic goat (Capra hircus) is the result of its medium size and high adaptability as multiple breeds. The extent to which its genetic variability was influenced by early domestication practices is largely unknown. A common standard by which to analyze maternally-inherited variability of livestock species is through complete sequencing of the entire mitogenome (mitochondrial DNA, mtDNA). RESULTS: We present the first extensive survey of goat mitogenomic variability based on 84 complete sequences selected from an initial collection of 758 samples that represent 60 different breeds of C. hircus, as well as its wild sister species, bezoar (Capra aegagrus) from Iran. Our phylogenetic analyses dated the most recent common ancestor of C. hircus to ~460,000 years (ka) ago and identified five distinctive domestic haplogroups (A, B1, C1a, D1 and G). More than 90 % of goats examined were in haplogroup A. These domestic lineages are predominantly nested within C. aegagrus branches, diverged concomitantly at the interface between the Epipaleolithic and early Neolithic periods, and underwent a dramatic expansion starting from ~12-10 ka ago. CONCLUSIONS: Domestic goat mitogenomes descended from a small number of founding haplotypes that underwent domestication after surviving the last glacial maximum in the Near Eastern refuges. All modern haplotypes A probably descended from a single (or at most a few closely related) female C. aegagrus. Zooarchaelogical data indicate that domestication first occurred in Southeastern Anatolia. Goats accompanying the first Neolithic migration waves into the Mediterranean were already characterized by two ancestral A and C variants. The ancient separation of the C branch (~130 ka ago) suggests a genetically distinct population that could have been involved in a second event of domestication. The novel diagnostic mutational motifs defined here, which distinguish wild and domestic haplogroups, could be used to understand phylogenetic relationships among modern breeds and ancient remains and to evaluate whether selection differentially affected mitochondrial genome variants during the development of economically important breeds.

Levels and variability of metals in soils of the province of Golestan (Iran).

Studying the concentration distribution of metals is necessary for soil pollution monitoring and maintaining environmental quality. To date, very little large-scale research has been performed to investigate metal contamination in developing countries. In this study, the content and spatial distributions of five metals (cadmium [Cd], copper [Cu], nickel [Ni], lead [Pb], and zinc [Zn]) were quantified based on 346 topsoil samples from 12 districts in the province of Golestan (northeast [NE] Iran). The concentration levels (mg/kg) of Cd, Cu, Pb, Ni and Zn varied from 0.02 to 0.36, 9.3 to 93.7, 6.8 to 44, 9.5 to 85.35, and 25 to 417.4, respectively. The average concentrations (mg/kg) obtained were as follows: Cd 0.12 ± 0.07, Cu 23.9 ± 9.07, Ni 34.88 ± 11.59, Pb 15.42 ± 5.81 and Zn 82.08 ± 30.87. Significant differences in the distribution of trace elements among districts were detected. The AzadShahr and BandarGaz districts displayed the highest metal concentrations. Greater metal values were obtained in the central, south, west, and NE areas, although Zn concentration was also high to the north of the province. Values of contamination factor and contamination degree indicated that the metal pollution level was on the order of Zn > Cd > Pb > Cu > Ni and that all of the metals belonged to a low or moderate pollution category. Ni and Cu levels derived from natural sources, whereas Cd, Pb, and Zn derived from anthropogenic activities with greater mean concentrations than reference concentrations.

Detecting hybridization between Iranian wild wolf (Canis lupus pallipes) and free-ranging domestic dog (Canis familiaris) by analysis of microsatellite markers.

The genetic threat due to hybridization with free-ranging dogs is one major concern in wolf conservation. The identification of hybrids and extent of hybridization is important in the conservation and management of wolf populations. Genetic variation was analyzed at 15 unlinked loci in 28 dogs, 28 wolves, four known hybrids, two black wolves, and one dog with abnormal traits in Iran. Pritchard's model, multivariate ordination by principal component analysis and neighbor joining clustering were used for population clustering and individual assignment. Analysis of genetic variation showed that genetic variability is high in both wolf and dog populations in Iran. Values of H(E) in dog and wolf samples ranged from 0.75-0.92 and 0.77-0.92, respectively. The results of AMOVA showed that the two groups of dog and wolf were significantly different (F(ST) = 0.05 and R(ST) = 0.36; P < 0.001). In each of the three methods, wolf and dog samples were separated into two distinct clusters. Two dark wolves were assigned to the wolf cluster. Also these models detected D32 (dog with abnormal traits) and some other samples, which were assigned to more than one cluster and could be a hybrid. This study is the beginning of a genetic study in wolf populations in Iran, and our results reveal that as in other countries, hybridization between wolves and dogs is sporadic in Iran and can be a threat to wolf populations if human perturbations increase.

Phylogeny and evolution of the genus Cervus (Cervidae, Mammalia) as revealed by complete mitochondrial genomes.

Mitochondrial DNA (mtDNA) lineages are recognized as important components of intra- and interspecific biodiversity, and allow to reveal colonization routes and phylogeographic structure of many taxa. Among these is the genus Cervus that is widely distributed across the Holarctic. We obtained sequences of complete mitochondrial genomes from 13 Cervus taxa and included them in global phylogenetic analyses of 71 Cervinae mitogenomes. The well-resolved phylogenetic trees confirmed Cervus to be monophyletic. Molecular dating based on several fossil calibration points revealed that ca. 2.6 Mya two main mitochondrial lineages of Cervus separated in Central Asia, the Western (including C. hanglu and C. elaphus) and the Eastern (comprising C. albirostris, C. canadensis and C. nippon). We also observed convergent changes in the composition of some mitochondrial genes in C. hanglu of the Western lineage and representatives of the Eastern lineage. Several subspecies of C. nippon and C. hanglu have accumulated a large portion of deleterious substitutions in their mitochondrial protein-coding genes, probably due to drift in the wake of decreasing population size. In contrast to previous studies, we found that the relic haplogroup B of C. elaphus was sister to all other red deer lineages and that the Middle-Eastern haplogroup E shared a common ancestor with the Balkan haplogroup C. Comparison of the mtDNA phylogenetic tree with a published nuclear genome tree may imply ancient introgressions of mtDNA between different Cervus species as well as from the common ancestor of South Asian deer, Rusa timorensis and R. unicolor, to the Cervus clade.

The goat domestication process inferred from large-scale mitochondrial DNA analysis of wild and domestic individuals.

The emergence of farming during the Neolithic transition, including the domestication of livestock, was a critical point in the evolution of human kind. The goat (Capra hircus) was one of the first domesticated ungulates. In this study, we compared the genetic diversity of domestic goats to that of the modern representatives of their wild ancestor, the bezoar, by analyzing 473 samples collected over the whole distribution range of the latter species. This partly confirms and significantly clarifies the goat domestication scenario already proposed by archaeological evidence. All of the mitochondrial DNA haplogroups found in current domestic goats have also been found in the bezoar. The geographic distribution of these haplogroups in the wild ancestor allowed the localization of the main domestication centers. We found no haplotype that could have been domesticated in the eastern half of the Iranian Plateau, nor further to the east. A signature of population expansion in bezoars of the C haplogroup suggests an early domestication center on the Central Iranian Plateau (Yazd and Kerman Provinces) and in the Southern Zagros (Fars Province), possibly corresponding to the management of wild flocks. However, the contribution of this center to the current domestic goat population is rather low (1.4%). We also found a second domestication center covering a large area in Eastern Anatolia, and possibly in Northern and Central Zagros. This last domestication center is the likely origin of almost all domestic goats today. This finding is consistent with archaeological data identifying Eastern Anatolia as an important domestication center.

Gazella arabica dareshurii: a remarkable relict population on Farur Island, Iran.

BACKGROUND: The islands in the Persian Gulf are home to several species of gazelles, i.e., Gazella bennettii, G. subgutturosa, and a new subspecies of Mountain gazelles which was discovered on Farur Island and described for the first time in 1993 as Gazella gazella dareshurii. Later, phylogenetic analyses showed that the Mountain gazelles consist of two species: G. gazella and G. arabica. As the Farur gazelles are more closely related to the Arabian forms of the Mountain gazelles, this subspecies is regarded to be G. arabica dareshurii. Until now, the origin of this subspecies has been an enigma. RESULTS: Here, we used mitochondrial cyt b, two nuclear introns (CHD2 and ZNF618), and morphological data to address this question by investigating the taxonomic position of the Farur gazelles. The results show that this population is monophyletic and split from other G. arabica populations probably 10,000 BP. CONCLUSIONS: It is a natural relict population that was trapped on the island due to the rising sea levels of the Persian Gulf after the Last Glacial Maximum. Intermittent drought and flooding are suggested to be the main factors balancing population growth in the absence of natural predators on this monsoon-influenced island. Conservation actions should focus on preserving the natural situation of the island (cease introducing mesquite tree and other invasive species, stop building new construction and roads, and caution in providing water sources and forage), and possibly introducing individuals to other islands (not inhabited by gazelles) or to fenced areas on the Iranian mainland (strictly isolated from other gazelle populations) when the population reaches the carrying capacity of the island.

Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory Gastrointestinal Stromal Tumors: A Phase 1b/2a Nonrandomized Clinical Trial.

IMPORTANCE: Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors. OBJECTIVE: To assess whether combining a type II KIT inhibitor with a conformation-complementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control. DESIGN, SETTING, AND PARTICIPANTS: A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020. INTERVENTIONS: Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal. MAIN OUTCOMES AND MEASURES: Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA. RESULTS: A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively. CONCLUSIONS AND RELEVANCE: In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02401815.

Evolution and taxonomy of the wild species of the genus Ovis (Mammalia, Artiodactyla, Bovidae).

New insights for the systematic and evolution of the wild sheep are provided by molecular phylogenies inferred from Maximum parsimony, Bayesian, Maximum likelihood, and Neighbor-Joining methods. The phylogeny of the wild sheep was based on cytochrome b sequences of 290 samples representative of most of the sub-species described in the genus Ovis. The result was confirmed by a combined tree based on cytochrome b and nuclear sequences for 79 Ovis samples representative of the robust clades established with mitochondrial data. Urial and mouflon, which are either considered as a single or two separate species, form two monophyletic groups (O. orientalis and O. vignei). Their hybrids appear in one or the other group, independently from their geographic origin. The European mouflon O. musimon is clearly in the O. orientalis clade. The others species, O. dalli, O. canadensis, O. nivicola, and O. ammon are monophyletic. The results support an Asiatic origin of the genus Ovis, followed by a migration to North America through North-Eastern Asia and the Bering Strait and a diversification of the genus in Eurasia less than 3 million years ago. Our results show that the evolution of the genus Ovis is a striking example of successive speciation events occurring along the migration routes propagating from the ancestral area.

Diversification and subspecies patterning of the goitered gazelle (Gazella subgutturosa) in Iran.

Goitered gazelles, Gazella subgutturosa, exist in arid and semiarid regions of Asia from the Middle to the Far East. Although large populations were present over a vast area until recently, a decline of the population as a result of hunting, poaching, and habitat loss led to the IUCN classification of G. subgutturosa as "vulnerable." We examined genetic diversity, structure, and phylogeny of G. subgutturosa using mitochondrial cytochrome b sequences from 18 geographically distant populations in Iran. The median-joining network of cyt b haplotypes indicated that three clades of goitered gazelles can be distinguished: a Middle Eastern clade west of the Zagros Mountains (and connected to populations in Turkey and Iraq), a Central Iranian clade (with connection to Azerbaijan), and an Asiatic clade in northeastern Iran (with connection to Turkmenistan, Uzbekistan, and other Asian countries as far as northeastern China and Mongolia). Based on our results, we argue that Iran is the center of diversification of goitered gazelles, due to the presence of large mountain ranges and deserts that lead to the separation of populations. In accordance with previous morphological studies, we identified the Asiatic clade as the subspecies G. s. yarkandensis, and the other two clades as the nominate form G. s. subgutturosa. The new genetic information for goitered gazelles in Iran provides the basis for future national conservation programs of this species.

Repeated hybridization of two closely related gazelle species (Gazella bennettii and Gazella subgutturosa) in central Iran.

Interspecific hybridization increasingly occurs in the course of anthropogenic actions, such as species translocations and introductions, and habitat modifications or occurs in sympatric species due to the shortage of conspecific mates. Compared with anthropogenically caused hybridization, natural hybridization is more difficult to prove, but both play an important role in conservation. In this study, we detected hybridization of two gazelle sister species, Gazella bennettii (adapted to dry areas) and Gazella subgutturosa (adapted to open plains), in five habitat areas, where G. bennettii naturally occur in central Iran. The hybrids have a nuclear genomic identity (based on two introns), habitat preference, and phenotype of G. bennettii, but the mitochondrial identity (based on cyt b) of G. subgutturosa. We suggest that natural hybridization of female G. subgutturosa and male G. bennettii happened twice in central Iran in prehistoric times, based on the haplotype pattern that we found. However, we found indications of recent hybridization between both species under special circumstances, for example, in breeding centers, due to translocations, or in areas of sympatry due to the shortage of conspecific mates. Therefore, these two species must be kept separately in the breeding centers, and introduction of one of them into the habitat of the other must be strictly avoided.

Predictive Value of Computed Tomography Scan for Posterior Ligamentous Complex Injuries in Patients with Thoracolumbar Spinal Fractures.

BACKGROUND: Thoracolumbar spinal fractures include a range of injuries of various severities from simple apophyseal fractures to neurological injury and complex fractures associated with vertebral dislocation. The treatment of thoracolumbar fractures is challenging, especially due to the difficulty of evaluating the posterior ligamentous complex (PLC). The purpose of this study was to evaluate the diagnostic value of computed tomography (CT) scan in predicting PLC injuries in the patients with thoracolumbar spinal fractures referring to the referral center of spinal trauma in the east north of Iran in 2016. METHODS: This retrospective study was conducted on patients with thoracolumbar injuries referring to Shahid Kamyab Hospital in Mashhad, east north of Iran, in 2016. The data were collected by entering the data of medical records into special forms. The classification of spinal fractures was accomplished using the AO Spine Classification System. RESULTS: According to the results, 71 (71.7%) patients were male, and the subjects had a mean age of 44.6±17.7 years. The PLC injury was observed in 28 (28.3%) patients. The PLC injury showed a significant relationship with facet joint widening, increased interspinous process distance, and spinous process avulsion fracture (P<0.05). CONCLUSION: As the findings of this study indicated, the diagnostic results of PLC injury by means of CT scan was similar to those obtained by magnetic resonance imaging in patients with thoracolumbar spinal fractures.

An evaluation of sequencing coverage and genotyping strategies to assess neutral and adaptive diversity.

Whole genome sequences (WGS) greatly increase our ability to precisely infer population genetic parameters, demographic processes, and selection signatures. However, WGS may still be not affordable for a representative number of individuals/populations. In this context, our goal was to assess the efficiency of several SNP genotyping strategies by testing their ability to accurately estimate parameters describing neutral diversity and to detect signatures of selection. We analysed 110 WGS at 12× coverage for four different species, i.e., sheep, goats and their wild counterparts. From these data we generated 946 data sets corresponding to random panels of 1K to 5M variants, commercial SNP chips and exome capture, for sample sizes of five to 48 individuals. We also extracted low-coverage genome resequencing of 1×, 2× and 5× by randomly subsampling reads from the 12× resequencing data. Globally, 5K to 10K random variants were enough for an accurate estimation of genome diversity. Conversely, commercial panels and exome capture displayed strong ascertainment biases. Besides the characterization of neutral diversity, the detection of the signature of selection and the accurate estimation of linkage disequilibrium (LD) required high-density panels of at least 1M variants. Finally, genotype likelihoods increased the quality of variant calling from low coverage resequencing but proportions of incorrect genotypes remained substantial, especially for heterozygote sites. Whole genome resequencing coverage of at least 5× appeared to be necessary for accurate assessment of genomic variations. These results have implications for studies seeking to deploy low-density SNP collections or genome scans across genetically diverse populations/species showing similar genetic characteristics and patterns of LD decay for a wide variety of purposes.

Sheep genome functional annotation reveals proximal regulatory elements contributed to the evolution of modern breeds.

Domestication fundamentally reshaped animal morphology, physiology and behaviour, offering the opportunity to investigate the molecular processes driving evolutionary change. Here we assess sheep domestication and artificial selection by comparing genome sequence from 43 modern breeds (Ovis aries) and their Asian mouflon ancestor (O. orientalis) to identify selection sweeps. Next, we provide a comparative functional annotation of the sheep genome, validated using experimental ChIP-Seq of sheep tissue. Using these annotations, we evaluate the impact of selection and domestication on regulatory sequences and find that sweeps are significantly enriched for protein coding genes, proximal regulatory elements of genes and genome features associated with active transcription. Finally, we find individual sites displaying strong allele frequency divergence are enriched for the same regulatory features. Our data demonstrate that remodelling of gene expression is likely to have been one of the evolutionary forces that drove phenotypic diversification of this common livestock species.

Convergent genomic signatures of domestication in sheep and goats.

The evolutionary basis of domestication has been a longstanding question and its genetic architecture is becoming more tractable as more domestic species become genome-enabled. Before becoming established worldwide, sheep and goats were domesticated in the fertile crescent 10,500 years before present (YBP) where their wild relatives remain. Here we sequence the genomes of wild Asiatic mouflon and Bezoar ibex in the sheep and goat domestication center and compare their genomes with that of domestics from local, traditional, and improved breeds. Among the genomic regions carrying selective sweeps differentiating domestic breeds from wild populations, which are associated among others to genes involved in nervous system, immunity and productivity traits, 20 are common to Capra and Ovis. The patterns of selection vary between species, suggesting that while common targets of selection related to domestication and improvement exist, different solutions have arisen to achieve similar phenotypic end-points within these closely related livestock species.

BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.