Experimental Hematology 2014;42:595–597

Editorial

A comment from the Editor-in-Chief, Dr. KeithHumphries. On behalf of the journal, I am very pleasedto introduce a special issue devoted to two exciting researchtopics of growing importance to our fielddGenomics,guest edited by Dr. Bertie Gottgens, and Model Organisms,guest edited by Dr. David Traver. This combined series ofreviews highlights recent advances across the wide rangeof model organisms and genome-scale approaches with aparticular emphasis on strategies that are showing promisefor extracting new biological insights relevant to normalhematopoiesis and disease. In the following, Drs. Gottgensand Traver provide a glimpse of the topics covered in theirrespective review series that I hope will encourage a deepread and discussion.

A special note of thanks to the many authors who soenthusiastically and kindly agreed to contribute to thisreview series.

Genomics (Guest Editor, Dr. Bertie Gottgens). Recentbreakthroughs in high-throughput sequencing technologyare rapidly making genome-scale experimentation acces-sible to mainstream laboratories engaged in hematologyresearch. Using these technologies, major advances havealready been made both in basic and translational research,ranging from genome-wide descriptions of chromatin andexpression states to complete catalogs of acquired muta-tions in several types of leukemia. Six reviews in this spe-cial issue of Experimental Hematology highlight recentadvances across a wide range of genome-scale approachescurrently used in experimental hematology research,focusing on two particular aims: 1) to emphasize the strate-gies that have shown promise in extracting new biologicalinsights from large datasets, and 2) to provide guidancefor those who are keen to take advantage of new genomictechnologies for their own research.

The first review introduces the use of next generationsequencing technology for cellular barcoding, where Naiket al [1] discuss the benefits and pitfalls of this new tech-nique. This article will be an interesting read for anyonewho wants to take advantage of this powerful technologyto quantitatively trace in vivo fate decisions made by indi-vidual stem or progenitor cells. The next review by Jeongand Goodell [2] focuses on DNA methylation in hematopoi-etic cells. The authors discuss the role of DNA methylationduring differentiation and the progression of myeloid malig-nancies. In addition to providing a comprehensive summaryof how and where DNA methylation takes place throughoutthe genome, the authors also highlight newly discovered

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mechanisms for the reversal of DNA methylation and focuson its role during diverse biological processes.

The next section then moves from genome-wide maps ofDNA methylation to genome-wide maps of transcriptionfactor binding. DeVilbiss et al [3] provide a concise sum-mary of the methodology and analysis of chromatin immu-noprecipitation and massive parallel sequencing. Theauthors highlight the importance of follow-up experimentsto attach likely ‘‘biological meaning’’ to distinct genome-wide binding patterns and discuss the important discoveriesthat have emerged during the progression from single-geneloci to genome-wide analysis. Furthermore, they focus onthe importance of integrating additional new technologiesas well as more established techniques for the communityto begin to fully comprehend the transcriptional mecha-nisms at play.

Genome-wide association studies (GWAS) represent arelatively mature genome-scale technology, which neverthe-less has provided exciting new insights relevant to experi-mental hematology in the last few years. The review byAna Cvejic [4] looks at several important advances that havebeen made through GWAS analysis, focusing specifically onfollow-up functional studies that have provided insight intonovel regulatory processes and implicated novel genes intohematopoiesis. The final two reviews of this section of thisspecial issue of Experimental Hematology cover the applica-tion of genome-scale approaches within the context of he-matologic malignancies. Continuing with the regulatorymechanism theme, Prange et al [5] discuss transcription fac-tor deregulation during leukemia. They also focus on themolecular role of these transcription factor complexes andthe interplay between these factors and the local epigeneticenvironment.

The final review focuses on gene expression profiling(GEP) in leukemia, with a specific focus on acute myeloidleukemia. Shivarov et al [6] discuss how GEP has led to abetter understanding of class prediction, class discovery,and improved outcome prediction. This review also focuseson the importance of integrating GEP datasets to provide amore comprehensive overview of disease, which has thepotential to improve the clinical management of hemato-logical diseases.

Model Organisms (Guest Editor, Dr. David Traver).Studies of developmental hematopoiesis have beeninformed through decades of experiments in a variety ofanimal systems. Comparative studies between animals haveelucidated many common themes in embryonic bloodcell formation. In all organisms studied, whether inverte-brate or vertebrate, developmental hematopoiesis proceeds

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through multiple waves, with different precursors specifiedin different tissues to generate different cell types. Ingeneral, the precursors specified earliest show the greatestrestriction in differentiation potential, generating onlylimited lineages of ‘‘primitive’’ hematopoietic cell types.Only in the later formed waves do ‘‘definitive’’ precursorsemerge that show multilineage potential and generate prog-eny that persist into adulthood. In this special issue ofExperimental Hematology, we present six reviews fromexperts in developmental hematopoiesis that focus on thepower of each of the major model systems in informingblood cell ontogeny. Each article provides the reader withboth a historic perspective on what has been learned in eachmodel and insight as to how the relative strengths of eachwill be further utilized to advance the field.

It has been clear for well over a century that there issomething special about the ventral domain of the dorsalaorta, in that clusters of hematopoietic cells are observedthere in all vertebrate animals studied [7]. What was notclear until recently is whether these blood cells derivedfrom local precursors born in or near the aorta, or whetherthe aorta functioned as a transitional site for migrating pre-cursors born elsewhere [8]. Early studies in the chicken em-bryo, where aortic endothelium was fluorescently labeledbefore the appearance of hematopoietic clusters, suggestedthat hematopoietic stem cells (HSCs) were born locallyfrom hemogenic endothelium present within the aortic floor[9]. In this issue, Jaffredo and Yvernogeau [10] summarizethese and other key findings, providing perspective on whatthe avian embryo has taught us about hematopoieticontogeny. Similarly, early studies in frogs demonstratedthat different regions of the developing embryo gave riseto hematopoietic precursors with different functional capac-ities. Taking advantage of the robust transplantation modal-ities that Xenopus embryos offer, cell transfer experimentsdemonstrated that long-term repopulating HSCs likewisederived from an intra-embryonic source, whereas precur-sors with transient repopulation capacity were born indistinct regions [11]. Ciau-Uitz et al [12] summarize thesefindings and elucidate the genetic hierarchies that specif-ically regulate HSC emergence during embryogenesis.Throughout this article are excellent comparisons betweenthe frog and fish embryo regarding early hematopoiesis,nicely highlighting the relative strengths of each system.

Continuing this discussion, Carroll and North [13] sum-marize the rapid emergence of the zebrafish in hematopoi-etic research. The authors describe how the facile geneticamenability, optical transparency coupled with fluorescenttransgenesis, and ease of chemical screening approacheshave collectively positioned the zebrafish as a powerful sys-tem in which to study hematopoietic stem and progenitorcells. Whereas most studies in the zebrafish have addressedhematopoietic ontogeny, recent studies have also begun toprobe immune cell function and the ways in which immu-nity is maintained relative to that in mammals. Norimasa

Iwanami [14] focuses on lymphocyte development andfunction in the zebrafish and provide an overview of howlymphoid-based immunity has evolved during the radiationof vertebrate species from a common ancestor. The authorsgive future perspectives as to how studies of immune func-tion and dysfunction in the zebrafish should complementthose performed in the mouse, the preeminent model forimmune cell study.

Decades of study in the murine system have led to a rela-tively precise understanding of hematopoietic stem and pro-genitor cell biology. Schmitt et al [15] summarize the broadutility of the mouse system, highlighting its many firsts,including demonstration of HSC function via robust trans-plantation assays, prospective isolation to purity of HSCs,powerful gene knock-out approaches, and creation of‘‘humanized’’ mice in which long-term hematopoiesis canbe achieved using transplanted human HSCs. A historicperspective on the developmental origin of murine HSCsis presented, reviewing the experiments that have led fromthe initial view that the adult hematopoietic system derivesfrom an extra-embryonic source to the current view that itderives from aortic hemogenic endothelium.

Finally, Gold and Br€uckner [16] provide a perspectiveon invertebrate hematopoiesis, summarizing key findingsin Drosophila that have helped inform how blood cell devel-opment has evolved over millennia. Notably, hematopoiesisin flies also proceeds through sequential waves duringembryogenesis, giving rise to two classes of myeloid cells.As has recently become appreciated in vertebrates [17],tissue macrophages in the fly are seeded during embryonicand larval stages, after which their populations are self-maintained without the need for replenishment by upstreamprogenitor cells. In this review, the formation and function ofthese cells are compared and contrasted to their vertebratecognates, highlighting how studies in simpler organismscan provide important information on how hematopoiesisand immunity have evolved across animal phyla.

R. Keith Humphries

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