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Getting to the Core of Inherited Bone Marrow Failures

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Getting to the Core of Inherited Bone Marrow Failures EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS 1. Department of Medicine, Duke Getting to the Core of Inherited Bone Marrow University Medical Center, Failures Durham, USA; 2. King Abdulaziz University, Jeddah, KSA; 3. Institute 1,2* 3* 4 of Genetic Medicine, Newcastle SOHEIR ADAM , DARIO MELGUIZO SANCHIS , GHADA EL‐KAMAH , 5 6 4 University, UK; 4. Division of Hu‐ SUJITH SAMARASINGHE , SAMEER ALHARTHI , LYLE ARMSTRONG 4# man Genetics & Genome Research, AND MAJLINDA LAKO National Research Center, Cairo, Egypt; 5. Department of Hematol‐ Key words. inherited bone marrow failures hESC hiPSC animal models ogy, Great Ormond Street Hospital for Children NHS Foundation Trust, ABSTRACT London, UK; 6. Princess Al Jawhara Al‐Brahim Center of Excellence in Bone marrow failure syndromes (BMFS) are a group of disorders with Research of Hereditary Disorders, complex pathophysiology characterized by a common phenotype of pe‐ King Abdulaziz University, KSA ripheral cytopenia and/or a hypoplastic bone marrow. Understanding ge‐ # to whom correspondence should netic factors contributing to the pathophysiology of BMFS has enabled the be addressed: Prof. Majlinda Lako, identification of causative genes and development of diagnostic tests. To Newcastle University, Institute of date more than 40 mutations in genes involved in maintenance of genomic Genetic Medicine, International stability, DNA repair, ribosome and telomere biology have been identified. Centre for Life, Newcastle NE1 3BZ, In addition, pathophysiological studies have provided insights into several UK, phone: 00 44 191 241 8688, biological pathways leading to the characterization of geno‐ Email: [email protected]; type/phenotype correlations as well as the development of diagnostic ap‐ *JOINT FIRST AUTHORS proaches and management strategies. Recent developments in bone mar‐ row transplant techniques and the choice of conditioning regimens have Received August 29, 2016; accept‐ helped improve transplant outcomes. However, current morbidity and ed for publication October 28, mortality remain unacceptable underlining the need for further research in 2016; available online without sub‐ this area. Studies in mice have largely been unable to mimic disease phe‐ scription through the open access notype in humans due to difficulties in fully replicating the human muta‐ option. tions and the differences between mouse and human cells with regard to telomere length regulation, processing of reactive oxygen species and ©AlphaMed Press lifespan. Recent advances in induced pluripotency have provided novel 1066‐5099/2016/$30.00/0 insights into disease pathogenesis and have generated excellent platforms for identifying signaling pathways and functional mapping of haplo‐ This article has been accepted for insufficient genes involved in large‐scale chromosomal deletions– publication and undergone full associated disorders. In this review we have summarized the current state peer review but has not been of knowledge in the field of BMFS with specific focus on modelling the in‐ through the copyediting, typeset‐ herited forms and how to best utilize these models for the development of ting, pagination and proofreading targeted therapies. STEM CELLS 2016; 00:000–000 process which may lead to differ‐ ences between this version and the SIGNIFICANCE STATEMENT: Version of Record. Please cite this article as doi: 10.1002/stem.2543 Bone marrow failure syndromes are characterized by a common phenotype of peripheral cytopenia and/or a hypoplastic bone marrow. Great strides have been made in the last twenty years both scientifically and clinically re‐ sulting in identification of more than 40 causative genes and improved transplant outcomes. In this review we summarise the most recent findings achieved through application of animal models and stem cells which have led to important insights in disease physiopathology and improved patient care. STEM CELLS 2016;00:00‐00 www.StemCells.com ©AlphaMed Press 2016 2 INTRODUCTION DBA, SCN & TAR present with single cytopenias that rarely become aplastic but have increased risks of leu‐ Bone marrow failure syndromes (BMFS) are rare dis‐ kemia. Solid tumors like head & neck and anogenital eases characterized by peripheral cytopenias and/or a squamous cell carcinoma are associated with FA & DC hypoplastic bone marrow and can either be inherited or and osteogenic sarcoma with DBA (4, 5). A summary of acquired (1‐3). The purpose of this review is to discuss the clinical features of these diseases together with the methods by which we may create in vitro models of associated mutations and therapeutic options is given in these conditions, therefore we will focus upon inherited Table 1 (6‐23). BMFS since although it is possible to induce bone mar‐ Although rare, the clinical impact of BMFS is un‐ row failure in experimental animals by administration of doubtedly significant. Experimental approaches to in‐ specific chemicals (1), the development of methods to crease our understanding of these disorders are thus replicate the phenotypes of acquired syndromes using essential. Moreover, since many of the causative genes cellular models is currently difficult. In essence, two play important roles in the development and mainte‐ broad mechanisms may be used to generate useful nance of the hematopoietic system, studying their dys‐ models of these diseases. Animal models can work well functions may provide further insights into the produc‐ in cases where the genetic causes of the disease are tion mechanisms of blood and immune cells. Thus in‐ known at the level of DNA sequence since it is feasible vestigations using animal and cellular models of the to engineer experimental animals in which the relevant group of diseases reviewed herein are of great value. mutations play analogous role to their human homo‐ logues. A significant problem with this approach is that Animal models of the bone marrow failure the physiology of experimental animal species is often a syndromes recapitulate only some disease poor match to that of humans and genes known to car‐ features ry disease causing mutations in humans may not always Several strategies may be applied to the generation of have exactly the same mechanistic role in animals such animal models of BMFS with murine models being most as mice or rats. An increasingly attractive alternative is typically applied. Genetically modified mice can be gen‐ the use of pluripotent stem cell technology to create in erated by either direct pronuclear injection of exoge‐ vitro models of disease. Typically, this will involve “re‐ nous DNA into fertilized zygotes or injection of genet‐ programming” patient somatic cells followed by differ‐ ically‐modified murine embryonic stem cells (ESC) into a entiation to the types of cells most affected by the dis‐ blastocyst. Direct pronuclear injection is technically ease. The behavior of these cells in vitro may replicate demanding and often results in multiple, random inte‐ many features of the disease making them a valuable grations of the injected DNA into the genome, and the tool for increasing our understanding and identifying resulting disease phenotypes can vary depending on the potential treatments. We will discuss both of these expression level of the injected transgene. Mouse ESCs modelling options in turn. have the advantage that they can be genetically modi‐ Bone marrow failure syndromes have a broad clini‐ fied by means of homologous recombination, a process cal spectrum, sharing the failure of hematopoietic stem by which a fragment of genomic DNA introduced into a cells (HSCs) to produce functional blood cells and can mammalian cell can recombine with the endogenous affect patients of all ages (1‐3). More than 30 inherited homologous sequence. This process is known as “gene BMFS have been described and although they are gen‐ targeting.” When such genetically modified ES cells are erally rare, conditions such as Fanconi Anemia (FA), introduced into a pre‐implantation embryo, they can Dyskeratosis Congenita (DKC), Diamond‐Blackfan Ane‐ contribute to all cell lineages of the resulting chimeric mia (DBA), Shwachman‐Diamond Syndrome (SDS), Con‐ animal. If this contribution also comprises germ cells genital Amegakaryocytic Thrombocytopenia (CAMT), and the chimeras are capable of breeding, it is possible Severe Congenital Neutropenia (SCN) and Thrombocy‐ to establish lines of animals that are both heterozygous topenia Absent Radii (TAR) are among the most com‐ and homozygous for the genetic alteration introduced mon types. To date, more than 40 mutations in genes into the ESCs. This process can be used to add DNA se‐ involved in maintenance of genomic stability, DNA re‐ quences to specific genomic loci (knock‐ins), a protocol pair and telomere biology have been identified in inher‐ most often used to generate cell lines with gene‐specific ited BMFS. In addition, pathophysiological studies have reporter systems (24), or to create point mutations with provided insights into several biological pathways un‐ pinpoint accuracy. The technology for generating raveling genotype/phenotype correlations, diagnostic mouse models using gene targeting is well developed approaches, and management strategies (1). Given the and while discussion of this technology is outside the association between BMFS and genes involved in DNA scope of this article, excellent reviews on the subject repair mechanisms, it is perhaps unsurprising that many are available (25‐27). of the BMFS have a high predisposition towards malig‐ nancy
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