Inherited Biallelic Loss-Of-Function Mutations In CSF3R Define a Novel Type Of Severe Congenital Neutropenia With Full Myeloid Cell Maturation and Refractoriness To RhG-CSF

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1025-1025
Author(s):  
Alexa Triot ◽  
Päivi M Järvinen ◽  
Juan I. Arostegui ◽  
Tomas Racek ◽  
Jacek Puchalka ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Morphological Variability ◽  
Myeloid Cell ◽  
Cell Maturation ◽  
Morphological Evidence ◽  
Compound Heterozygous ◽  
Neutrophil Granulocytes ◽  
Severe Congenital Neutropenia ◽  
Loss Of Function ◽  
Congenital Neutropenia

Abstract Severe congenital neutropenia (SCN) is a heterogeneous group of disorders characterized by defective production and viability of neutrophil granulocytes and predisposition to life-threatening bacterial infections. Currently, OMIM lists five defined monogenic SCN: SCN1 ELANE, SCN2 GFI1, SCN3 HAX1, SCN4 G6PC3. Here, we describe a novel SCN subtype (SCN6) caused by recessively-inherited loss-of-function mutations in the gene encoding the granulocyte colony-stimulating receptor (CSF3R). We have identified four affected children in two distinct families. Family A had a homozygous missense mutation in close proximity of the highly conserved WSXWS motif (c.922T, p.Arg308Cys) and family B had two compound heterozygous small deletions provoking frameshift mutations (p.Gly316fs and p.Gly415fs). Mutated G-CSFR p.Arg308Cys protein was characterized by perturbed N-glycosylation and aberrant localization to cell surface. G-CSF induced phosphorylation of STAT3 and STAT5 was greatly diminished. In contrast to other SCN subtypes, all patients had morphological evidence of full myeloid cell maturation in bone marrow. However, none of the patients responded to granulocyte colony-stimulating growth factor (GCSF) treatment in vivo, confirming aberrant GCSF-receptor dependent signaling. Our studies highlight the genetic and morphological variability of SCN and provide evidence both for functional importance and redundancy of G-CSFR-mediated signaling in human granulopoiesis. Disclosures: No relevant conflicts of interest to declare.

Deficiency Of JAGN1 Causes Severe Congenital Neutropenia Associated With Defective Secretory Pathway and Aberrant Myeloid Cell Homeostasis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 439-439
Author(s):  
Kaan Boztug ◽  
Päivi M Järvinen ◽  
Elisabeth Salzer ◽  
Tomas Racek ◽  
Sebastian Mönch ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Conflicts Of Interest ◽  
Snp Array ◽  
Neutrophil Granulocytes ◽  
Homozygous Mutation ◽  
Genetic Linkage Analysis ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Gene Encoding ◽  
Consistent Finding

Abstract Analysis of patients with severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling differentiation, maintenance, and decay of neutrophil granulocytes. Mutations in ELANE, GFI1, HAX1, G6PC3, WAS, and VPS45 are known to cause SCN. We here describe a new monogenetic SCN variant with biallelic mutations in the gene encoding Jagunal homolog 1 (JAGN1). We studied an index family from Northern Africa with a total of 5 children suffering from SCN. An Affymetrix SNP array-based genetic linkage analysis was performed and identified a single interval of perfect segregation with highly significant multi-marker LOD scores of at least 4.5spanning approximately 1.5Mbp from 9.52Mb to 11.04Mb on chromosome 3 of NCBI’s human genome build 36.3. This interval contained a total of 30 genes, including JAGN1 which encodes an ER-resident protein. Sanger sequencing revealed a homozygous mutation c.3G>A in exon 1 of the JAGN1 gene; this mutation leads to disruption of the defined start of translation. Systematic analysis of a cohort of 90 SCN patients identified 9 distinct homozygous mutations in the gene encoding Jagunal homolog 1 (JAGN1) in 14 SCN patients, thus accounting for approximately 10% of SCN patients. The clinical phenotype was variable and included failure to thrive, developmental delay and bone skeletal abnormalities. The only consistent finding in all JAGN1-deficient patients was SCN and partial or complete refractoriness to therapy with rh-GCSF. JAGN1 is the human ortholog of a gene originally identified in Drosophila melanogaster. Jagunal-deficient oocytes are characterized by defective ER reorganization and aberrant membrane trafficking during vitellogenesis. We found that JAGN1-mutant human granulocytes showed aberrantly enlarged ER structures and paucity of secretory vesicles. We hypothesized that that ER aberrations may be associated with defective N-glycosylation of multiple proteins in neutrophil granulocytes and found that JAGN1-mutant neutrophil granulocytes exhibited anomalous N-glycomic profiles characterized by a marked reduction in fucosylation of all their multi-antennary glycans. JAGN1-deficient neutrophil granulocytes showed increased apoptosis in response to TNFa and staurosporine, likely accounting for the lack of mature neutrophils in these patients. Additional studies in JAGN1-knockdown cells indicate that JAGN1 participates in the secretory pathway and is required for granulocyte-colony stimulating factor receptor-mediated signaling. Global proteomic analysis of the JAGN1-interactome identified a limited number of interaction partners including members of the Coat Protein I (COPI) complex (COPA, COPB2, and COPG2) which suggest a role for JAGN1 in vesicular trafficking from Golgi to ER. Taken together, JAGN1 emerges as a hitherto unrecognized factor necessary in differentiation and survival of neutrophil granulocytes and a novel gene implicated in SCN. Disclosures: No relevant conflicts of interest to declare.

Mechanism of the Elevated UPR in CN Patients but Not in CyN Patients Carrying Same ELANE Mutations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 14-14
Author(s):  
Rainer Nustede ◽  
Inna Kuznetsova ◽  
Karl Welte ◽  
Julia Skokowa
Keyword(s):  
Cell Lines ◽  
Mammalian Cells ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Severe Congenital Neutropenia ◽  
Healthy Individuals ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia

Abstract Abstract 14 Several studies found that in patients with severe congenital neutropenia (CN) harboring mutations in the ELANE gene mutated NE protein induced unfolded protein response (UPR) leading to elevated apoptosis and diminished differentiation of myeloid cells. However, it is unclear, why UPR was not detected in patients with cyclic neutropenia (CyN) carrying the same ELANE mutations, which have been found in CN patients. Several UPR components have been identified in mammalian cells, which include three transducers (IRE1, PERK, and activating transcription factor 6 (ATF-6) as well as one master regulator (BiP/GRP78). BiP is known to be regulated by ATF6. The activation of ATF6 and its target genes (GADD34, CHOP and BiP) in CN patients has not been studied yet. We were able to detect significantly elevated levels of ATF6 and BiP in myeloid cells of CN patients with ELANE mutations, in comparison to CyN patients and to healthy individuals. Therefore, we investigated the mechanism of UPR and activation of ATF6 and ATF6 target genes in CN patients in comparison to CyN patients. We transduced the myeloid cell lines HL60 and NB4 with lentiviral constructs contained either wild type (WT) ELANE cDNA, or mutated (MUT) ELANE cDNA and measured mRNA and protein expression of ATF6 as well as mRNA expression of ATF6 target genes. We compared the effects of three ELANE mutations: C42R, V145-C152del (both mutations presented in CN patients, but not in CyN patients) and S97L (typical for CN and CyN patients) with WT ELANE. We found that in both cell lines only C42R ELANE MUT, but not V145-C152del ELANE MUT or S97L ELANE MUT induced expression of ATF6, GADD34, CHOP and BiP, as compared to control transduced cells. Furthermore, we hypothesize that degradation of mutated NE protein by Secretory Leukocyte Protease Inhibitor (SLPI) might be involved in UPR induction. However, we detected only very low levels of SLPI mRNA in CD33+ myeloid cells and in PMNs of patients with severe congenital neutropenia (CN), as compared to patients with cyclic neutropenia (CyN) and to healthy individuals. The lack of the NE inhibitor, SLPI in CN patients may further contribute to elevated UPR triggered by ELANE MUT and normal levels of SLPI in CyN patients might protect from ELANE MUT-induced UPR. Indeed, inhibition of SLPI using SLPI-specific shRNA led to a significantly elevated expression levels of ATF6, GADD34 and BIP, as compared to ctrl shRNA transduced cells. More importantly, co-transduction of NB4 cells with SLPI shRNA in combination with ELANE S97L MUT (which is common for both CN and CyN patients), but not with WT ELANE led to elevated levels of ATF6, GADD34 and BIP. In summary, different ELANE mutations have different effects on UPR as judged by ATF6 activation and the level of ELANE-triggered UPR is regulated by SLPI. Disclosures: No relevant conflicts of interest to declare.

mRNA and Protein Expression Levels of Secretory Leukocyte Protease Inhibitor (SLPI) Are Severely Reduced in Patients with Severe Congenital Neutropenia (CN)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2165-2165
Author(s):  
Wienke Ellerbeck ◽  
Olga Klimenkova ◽  
Julia Skokowa ◽  
Karl Welte
Keyword(s):  
Protease Inhibitor ◽  
Cell Line ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Myeloid Differentiation ◽  
Severe Congenital Neutropenia ◽  
Healthy Individuals ◽  
Congenital Neutropenia ◽  
Protein Levels ◽  
Myeloid Cell Line

Abstract Abstract 2165 Secretory Leukocyte Protease Inhibitor (SLPI) is a cationic serine protease inhibitor with antiprotease, primarily anti-Neutrophil ELastase (NE), activities. Moreover, SLPI modulates intracellular signal transduction pathways such as NF-kB and Erk. The molecular interaction and the balance between NE and SLPI is tightly regulated. On the one side, NE upregulates the SLPI expression and at the other hand SLPI inhibits the NE-induced degradation of proteins. We identified severe diminished levels of SLPI mRNA in CD33+ myeloid cells and in PMNs of patients with severe congenital neutropenia (CN) harbouring either ELANE or HAX1 mutations, as compared to patients with cyclic neutropenia (CyN) and to healthy individuals. SLPI protein levels in plasma of CN patients were also significantly reduced. We further analysed whether diminished levels of SLPI are associated with the „maturation arrest“ of myeloid cells seen in CN patients. We inhibited SLPI using lentivirus-based transduction of the myeloid cell line NB4 with SLPI-specific shRNA and analysed ATRA-triggered myeloid differentiation. Indeed, myeloid differentiation was severely affected in NB4 cells transduced with SLPI-specific shRNA, as compared to control shRNA transduced cells. Further, we analysed the mechanisms leading to SLPI downregulation. Previously, we identified severely reduced mRNA and protein levels of NE in myeloid cells and in plasma of CN patients with either ELANE or HAX1 mutations, as compared to healthy individuals. Knowing that NE induces SLPI expression, we assumed that diminished NE levels may be responsible for the low SLPI expression in CN patients. Indeed, inhibition of NE in the myeloid cell line NB4 using NE-specific shRNAs led to diminished expression of SLPI mRNA, as compared to ctrl shRNA transduced cells. At the same time, we also found that transduction of the myeloid cell line NB4 with wild type (WT) NE resulted in the increased expression of SLPI mRNA but mutated (MUT) forms of NE as found in CN patients were not able to induce SLPI mRNA, as compared to ctrl transduced cells. Taken together, both diminished NE levels and mutations in ELANE gene may cause downregulation of SLPI. In summary, SLPI is severely downregulated in CN patients due to defective NE protein levels and ELANE mutations. As a consequence, the anti-microbial and antiinflammatory activities of SLPI are diminished in CN patients. Disclosures: No relevant conflicts of interest to declare.

Novel NGS-Based Platforms For Molecular Diagnosis Of Severe Congenital Neutropenia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1034-1034
Author(s):  
Tomas Racek ◽  
Jacek Puchalka ◽  
Naschla Kohistani ◽  
Christoph Klein
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnostic ◽  
Compound Heterozygous ◽  
Neutrophil Granulocytes ◽  
Diagnostic Strategy ◽  
Congenital Neutropenia ◽  
Coding Regions ◽  
Whole Exome ◽  
Custom Made

Abstract Congenital neutropenia (CN) is a heterogeneous disorder. More than 30 distinct genetic defects have been discovered in patients with genetic diseases associated with decreased numbers of peripheral neutrophil granulocytes. Currently, most molecular diagnostic laboratories use Sanger-based sequencing techniques to define disease-causing mutations in patients with CN. In approximately 50% of patients no known genetic disorder can be found. To identify novel genes that can be causative for unexplained CN cases we embarked on next-generation whole-exome sequencing using SOLiD 5500™ and Ion Proton™ sequencers. Up to date we sequenced whole exomes of 49 families, in which children were diagnosed with CN. The fragment libraries were constructed using the SureSelect™ V4+UTRs System (Agilent) allowing us to target whole coding sequence and the majority of UTRs of human genome (approx. 71 Mb). The vast majority of the families were analysed in the “Trio” approach and suitable homozygous or compound heterozygous rare variations (frequency below 1%) in protein coding regions or in splice sites were chosen for further validations. In seven cases mutations previously described as causative for neutropenia were identified including G6PC3, HAX1, and ELANE. Four other rare variants are currently being analysed for their potential to cause CN. In 35 patients, no plausible candidate could be identified so far. When we assessed variants within the genes related to CN, our data revealed unequal coverage pattern over these genes. Around 10% of the exons were insufficiently covered (coverage of less than 10) to allow for reliable variant and genotype call. These facts limit the power of whole exome sequencing as a diagnostic tool, as mutations at the non-covered positions cannot be ruled out, and demonstrate the need of an alternative comprehensive approach. We are currently assessing sensitivity and specificity of a robust, rapid, and cost-effective approach that comprehensively analyses the sequence of 34 CN-relevant genes. Our approach is based on enrichment of specific exon regions by amplification using custom made AmpliSeq™ (Life Technologies) panel. For 25 genes we are able to sequence coding region as well as both UTR sequences, for 9 genes sequencing is limited to coding regions. This approach will provide a reliable, quick, and inexpensive diagnostic strategy for CN patients which will be offered free-of-charge to patients worldwide, independent of ethnic, national, or financial considerations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hax1 regulates neutrophil adhesion and motility through RhoA

2011 ◽  
Vol 193 (3) ◽  
pp. 465-473 ◽  
Author(s):  
Peter J. Cavnar ◽  
Erwin Berthier ◽  
David J. Beebe ◽  
Anna Huttenlocher
Keyword(s):  
Adaptor Protein ◽  
Neutrophil Function ◽  
Negative Regulator ◽  
Neutrophil Adhesion ◽  
Severe Congenital Neutropenia ◽  
Loss Of Function ◽  
Congenital Neutropenia ◽  
Rhoa Activity ◽  
Protein X ◽  
Kostmann Disease

Kostmann disease is an inherited severe congenital neutropenia syndrome associated with loss-of-function mutations in an adaptor protein HS1-associated protein X-1 (Hax1). How Hax1 regulates neutrophil function remains largely unknown. In this paper, we use ribonucleic acid interference to deplete Hax1 in the neutrophil-like cell line PLB-985 and identify Hax1 as a negative regulator of integrin-mediated adhesion and chemotaxis. Using microfluidics, we show that depletion of Hax1 impairs neutrophil uropod detachment and directed migration. Hax1-deficient cells also display increased integrin-mediated adhesion and reduced RhoA activity. Moreover, depletion of RhoA induces increased neutrophil adhesion and impaired migration, suggesting that Hax1 regulates neutrophil adhesion and chemotaxis through RhoA. Accordingly, activation of RhoA is sufficient to rescue adhesion of Hax1-deficient neutrophils. Together, our findings identify Hax1 as a novel regulator of neutrophil uropod detachment and chemotaxis through RhoA.

Incidence of SCN-Assoicated Gene Mutations in Severe Congenital Neutropenia Patients in North America

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3553-3553
Author(s):  
Jun Xia ◽  
Audrey Anna Bolyard ◽  
Elin Rodger ◽  
Steven Stein ◽  
Andrew AG Aprikyan ◽  
...  
Keyword(s):  
North America ◽  
North American ◽  
Barth Syndrome ◽  
North American Population ◽  
Compound Heterozygous ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia ◽  
The North ◽  
Two Samples

Abstract Severe congenital neutropenia is a genetically heterogeneous syndrome associated with mutations in several different genes including ELA2, HAX1, GFI1, WAS, and CSF3R. The goal of this study was to define the mutation frequency of these genes in the North American SCN patient population. We also sequenced SBDS, since mutations of SBDS have been associated with congenital and acquired neutropenia. A total of 159 patients were identified in the North American Severe Chronic Neutropenia International Registry (SCNIR) for whom informed consent and genomic DNA samples adequate for sequencing were available. To accommodate our semi-automated high-throughput sequencing pipeline, 94 samples were chosen for sequencing. Since ELA2 sequencing had already been performed in most cases, preference was given to those samples without known ELA2 mutation. Among the samples, 73 were from patients with SCN, 4 with cyclic neutropenia, 10 with idiopathic neutropenia, 2 with Shwachman-Diamond Syndrome (SDS), and 3 with Barth syndrome. Two samples were excluded because of poor sequence quality. Singleton cases with validated mutations of GFI1 (N382S) and WAS (L270P) were observed. The N382S GFI1 mutation was associated with striking monocytosis. A novel nonsense mutation of GFI1 (R412X) was detected in one additional case. As expected, compound heterozygous mutations of SBDS were present in the two cases of SDS. In addition, heterozygous mutations of SBDS (84Cfs3X and Q94X) were observed in two cases of SCN. Typical truncation mutations of CSF3R were detected in 4 cases, all developing MDS or AML. Surprisingly, no mutations of HAX1 were detected. Considering only patients with a diagnosis of SCN who were from North America (125 of the total 159 cases), the incidence of ELA2 mutations was 68%. Eleven novel ELA2 mutations were identified. In 28.8% of cases, no mutation of any gene were detected. Based on these data, we recommend that ELA2 genotyping be performed in all patients with suspected SCN. In the North American population mutations in HAX1, GFI1, SBDS, and WAS are rare and routine genotyping is not indicated. Finally, the data suggest that there are yet undiscovered genetic causes of SCN.

High Insta High Instability Of The CSF3R Gene In Severe Congenital Neutropenia Patients As Judged By Multiple CSF3R Mutations In The Majority Of Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2264-2264
Author(s):  
Maksim Klimiankou ◽  
Murat Uenalan ◽  
Siarhei Kandabarau ◽  
Lutz Wiehlmann ◽  
Anna-Lena Hagemann ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Conflicts Of Interest ◽  
Cell Clone ◽  
Stop Codon ◽  
Severe Congenital Neutropenia ◽  
Sequencing Data ◽  
Congenital Neutropenia ◽  
Cyclic Neutropenia ◽  
Extracellular Region ◽  
Inherited Mutations

Abstract It has been reported by us and others that approx. 30 % of all patients with congenital neutropenia (CN) acquire CSF3R mutations in their life time. More than 80 % of the CN patients who develop myeloid leukemia (CN/AML) harbour CSF3R mutations. This suggests that they are the first hit in leukemogenesis. However, detecting sequence changes e.g. by Sanger sequencing reveals only mutations presented in more than 20 % of the cells due to its technical detection limit. Therefore, we asked whether there is a systematic underestimation of cell clones harbouring CSF3R mutations, which might have been traditionally overlooked. We applied the deep-sequencing technology (SOLID 5500xl) to identify CSF3R mutations in myeloid cells from 158 patients with different types of neutropenia (86 severe congenital neutropenia (CN) patients with known inherited mutations (ELANE, HAX1, G6PC3), 21 cyclic neutropenia (CyN) patients, 28 patients with severe chronic neutropenia with so far unknown inherited mutations, 11 patients with SBDS-associated neutropenia) as well as a group of 12 healthy individuals. All neutropenia patients were treated with G-CSF and notably 21 CN patients developed leukemia or MDS. Deep sequencing data were processed according to our custom NGS pipeline (annotation of sequences and prediction of damaging effects on the coding sequence by Polyphen2, removal of known dbSNP variants, and accepting significant Phred-scores at the variant calling stage). Overall the read numbers ranged between 18 and 128069 (median 716), while only variants with at least two percent of the reads were accepted for further consideration (the statistically significant limit is between one and two percent of all reads). All together, we detected 92 CSF3R mutations in 42 CN patients leading to 49 distinct amino acid exchanges (38 missense and 11 stop-codon mutations). The frequency of the mutant alleles ranged from 2 to 96 %. In contrast, in CyN only five out of 21 patients harbour CSF3R mutations; interestingly, two of them in isoform IV of CSF3R (p.P752T). Most notably, whereas 18 patients displayed only one CSF3R mutation, 24 individuals had more than one CSF3R mutation (2-10 mutations, in total 74 mutations). During follow up of some patients, we could demonstrate that the number of mutations increased over time. The majority of mutations were located in the cytoplasmatic region (aa 651-831) of CSF3R, while 15 patients presented mutations within the extracellular region of CSF3R. Intriguingly, in 16 patients we detected 23 non-sense mutations, where 20 of these are stop-codon mutations affecting glutamine (Q) 768, 770, 776, and 781. This suggests that this part of CSF3R is highly instable. In two patients who did not respond to Filgrastim treatment, we detected a stop codon at aa 546 and 547, respectively, affecting the Fibronectin type-III like part of the CSF3R. Twelve patients who developed leukemia (CN/AML) had more than one CSF3R mutations (two to ten) , whereas eight with CN/AML harbored only one mutation. None of the healthy controls, only three neutropenia patients with unknown inheritance, and only one SBDS patient revealed mutations in CSF3R. Taken together, this data suggests that CSF3R is highly prone to genetic instability in severe congenital neutropenia, because more than one mutation in half of the patients was observed and various CSF3R mutations during the course of life accumulated. Once a cell clone harboring CSF3R mutation obtains a second hit (e.g. RUNX1 mutation), they are prone to undergo leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

MicroRNA Regulation of Immune Cell Development and Function

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-31-SCI-31
Author(s):  
Dinesh S. Rao
Keyword(s):  
Immune Cell ◽  
Conflicts Of Interest ◽  
Myeloid Cell ◽  
Cell Development ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Nf Kappa B ◽  
Hematopoietic Development ◽  
Myeloid Development ◽  
And Function

Abstract Abstract SCI-31 The NF-kappa B pathway is a central mediator of inflammation and plays an important role in myeloid cell development. During activation of macrophages by LPS, three microRNAs (miRNAs) were initially identified as being upregulated in an NF-kappa B dependent manner. Subsequent efforts to characterize two of these miRNAs, namely miR-155 and miR-146a, have revealed important roles not only in inflammation but also in hematopoietic development. Curiously, these two miRNAs seem to play opposing roles in promoting immune cell and progenitor proliferation, and the phenotypes induced in gain and loss-of-function contexts will be discussed in detail. Specifically, miR-155 overexpression and miR-146a deficiency lead to myeloid proliferations with pathologic consequences. These differential roles are largely explained by the targets of these microRNAs, which include signal transduction regulators: SHIP1 and SOCS1 in the case of miR-155, and TRAF6 and IRAK1 in the case of miR-146a. The roles of these miRNAs as effector and feedback regulator of the NF-kappa B pathway, respectively, will be discussed in the context of myeloid development. More broadly, these studies, as well as studies of miRNAs in B-cell development, have revealed that understanding miRNA roles in these processes will illuminate new aspects of biology and pathology. For example, the regulation of hematopoietic development by these miRNAs has revealed important interconnections between pathways that previously may have been considered disparate. Moreover, these studies have begun to underscore the importance of identifying specific targets of a miRNA in a given physiologic or pathologic context. Disclosures: No relevant conflicts of interest to declare.

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