Our understanding of the role of neutrophil-specific genes has been enhanced by the study of mice in which targeted disruption of a gene results in phenotypically important defects in neutrophil differentiation and function. Similarly, their importance has been underscored by the analysis of naturally occurring genetic events within these genes that result in human disease. The links between some genes and the diseases induced by their dysfunction may be anticipated by their important roles in neutrophil differentiation and function, whereas the pathophysiologic links of other genes to disease remain elusive (Table 1).

Table1. Differentiation-Specific Genes Implicated in Neutrophil Disorders

Disruption of neutrophil transcriptional regulation is a recurring theme in the pathogenesis of leukemia. Nearly half of patients with AML have pathognomonic translocations resulting in the fusion of a transcription factor with a tissue-specific gene. These translocations have been shown to interfere with appropriate myeloid differentiation and emphasize the role of transcription factors in that process.

As discussed previously, the same transcription factors that are implicated in the induction of neutrophil differentiation also direct the expression of genes encoding neutrophil-specific functional proteins. The link between morphologic differentiation and synthesis of neutrophil functional proteins is illustrated by the observation that disruption of C/EBPε signaling results in SGD, associated with both morphologic abnormalities and increased infections attributable to neutrophil functional defects. C/EBPε−/− mice share these abnormalities while also demonstrating a predilection for the development of myelodysplasia. Although the development of myelodysplastic syndrome (MDS) or AML has not been reported in patients with SGD, long-term follow-up is limited because SGD is a rare disease described in only fewer than a dozen patients.

Other diseases have been linked to defects in functionally important neutrophil proteins. Abnormalities in integrin expression, notably loss of the common β-chain of the integrin receptors, result in leukocyte adhesion deficiency, whereas absence of any one of the components of the reduced NADPH oxidase complex leads to chronic granulomatous disease.

Abnormalities in granule protein gene expression again underscore the complexity of the granulocyte functional program. Congenital absence of many individual granule proteins, including MPO, LF, and transcobalamin, has been described. In the absence of the more global defects seen in SGD, which presumably reflect more complex abnormalities than simple protein deficiency, these defects tend to be observed as incidental laboratory findings with minimal or no associated pathology.

One prominent exception is the association between point mutations in the ELANE gene (previously known as ELA2, which encodes NE) and SCN. The pathogenesis of SCN originally was attributed to defects in G-CSFR, supported by the observation of a truncation mutation in G-CSFR in select patients with Kostmann syndrome (reviewed by Berliner). It was later found that these were instead acquired mutations that may predispose the patient to secondary AML but by themselves did not constitute the pathologic basis for SCN.

Severe Congenital Neutropenia and the Unfolded Protein Response

SCN is a rare BM failure syndrome characterized by maturation arrest at the promyelocyte/myelocyte stage during neutrophil maturation in the BM (reviewed by Coffman and Lichtinger et al.). Because of profound neutropenia, the disease was almost uniformly fatal as a result of bacterial infections prior to the advent of G-CSF therapy (reviewed by Calkhoven et al.). In addition to having an increased risk of infection, patients with SCN treated with G-CSF also have an underlying predisposition for the later development of MDS/AML (reviewed by Lichtinger et al.). Although originally described as an autosomal recessive disorder, SCN is genetically heterogeneous, with multiple modes of inheritance including autosomal recessive (30% of patients), autosomal dominant (60% of patients), X-linked, and sporadic. Pathogenic mutations associated with SCN have been identified in a number of genes, including ELANE, HAX1, GFI1, WAS, CSF3R, and G6PC3 (reviewed by Coffman). Regardless of the mode of inheritance or gene mutation, newborns with SCN present with severe neutropenia. In contrast, patients with cyclic neutropenia (CN) have regular and consistent oscillations of their circulating neutrophils, with a mean cycle of 21 days. Patients with CN tend to have milder symptoms that often manifest later in life, respond well to lower doses of G-CSF, and do not progress to developing MDS/AML.

Mutations in ELANE, which encodes the primary granule protein NE, are the most common causes of both SCN (35% to 60%) and CN (80% to 100%). More than 200 distinct pathologic mutations in ELANE have been identified, spanning the entire coding sequence, and which occur in both patients with SCN and with CN with autosomal dominant inheritance. These mutations cause structural impairments in NE, leading to protein misfolding and intracellular mislocalization and accumulation. As a result, ER stress occurs, activating the unfolded protein response (UPR) and causing apoptosis within the granulocyte compartment. Different ELANE mutations appear to impact NE processing and trigger UPR activation to varying degrees, accounting for differences in disease severity and, in particular, the milder phenotype associated with CN.

Role of MicroRNAs in Controlling Gene Expression in Granulopoiesis

MicroRNAs (miRNAs) are 18- to 24-nucleotide-long noncoding RNAs that regulate eukaryotic gene expression by binding to specific sites in the 3′ UTR of target genes and altering expression by destabilizing mRNA or blocking mRNA translation. miRNAs are encoded in the genome and are transcribed by RNA polymerase II as long primary transcripts referred to as primary miRNAs (pri-miRNAs). These transcripts are recognized and processed by a ribonuclease, Drosha, into 60- to 80-nucleotide intermediates called precursor miRNAs (pre miRNAs), which are then exported to the cytoplasm, where a second ribonuclease, Dicer, cleaves pre-miRNAs to generate double-stranded miRNAs. The miRNAs are then incorporated into the RNA-induced silencing complex (RISC), a large protein complex that also contains the Argonaute or mRNA-cleaving proteins. The miRNA guides the RISC complex to target complementary regions in the 3′ UTRs of mRNAs, leading to repression of translation or mRNA destabilization by deadenylation (reviewed by Manikandan et al.).

An increasing body of evidence implicates miRNA activity in mediating both normal and abnormal myelopoiesis (reviewed by Pelosi et al.). miRNAs have been shown to activate or be activated by myeloid-specific transcription factors such as C/EBPα and Gfi-1. For example, miR-223 is thought to be a direct target of C/EBPα, and its expression increases during granulopoiesis. Ablating miR-223 in mice results in the expansion of granulocyte precursor cells resulting from a cell-autonomous increase in the number of granulocytic progenitors. In addition, overexpression of miR-223 in acute pro myelocytic leukemia (APL) cells results in an enhanced capacity for granulocytic differentiation. miR-223 is thus thought to be a positive regulator of granulopoietic differentiation. In addition, miR-223 targets E2F1, a master cell cycle regulator, by inhibiting translation of its mRNA. Thus granulopoiesis appears to be regulated by a C/ EBPα–miR-223–E2F1 axis, wherein miR-223 functions as a key regulator of myeloid cell proliferation associated with E2F1 in a mutual negative feedback loop.

Eiring et al. have demonstrated another role for miRNAs in granulopoiesis by demonstrating that miR-328 is downregulated in CML patients in blast crisis. miR-328 expression restores differentiation by interaction with both the C/EBPα translational inhibitor hnRNP E2 and the mRNA for PIM1, a survival factor. The interaction with hnRNP-E2 leads to the release of CEBPA mRNA from hnRNA-E2 mediated translational inhibition through an interaction that is independent of its seed sequence. miR-328 appears to control cell fate by its ability to base pair with the 3′ UTR of target mRNAs (PIM1) as well as by acting as a decoy for hnRNP binding, thus interfering with cell fate by releasing C/EBPα from translational inhibition.

A role for miR-27 in granulopoiesis has also been documented. miR-27 targets the myeloid transcription factor RUNX1, leading to decreased expression during granulocytic differentiation. Anti–miR 27 treatment of immature myeloid progenitors resulted in an increase in the expression of RUNX1 and impaired granulocytic differentia tion. In a separate study, the transcription factor Gfi-1 was shown to bind to the promoter of miR-196b and repress its expression, thereby promoting granulocytic maturation while repressing monocytic lineage development. Overexpression of miR-196b blocked granulopoi esis in granulocyte monocyte precursors (GMPs).

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مواضيع ذات صلة

Genes Can Be Identified by Their Map Position on the Chromosome

Homologous Recombination Can Repair DNA Damage and Generate Genetic Diversity

During Chain Elongation Each Incoming Aminoacyl-tRNA Moves Through Three Ribosomal Sites

Eukaryotic Translation Initiation Usually Occurs at the First AUG Downstream from the 5′ End of an mRNA

Ribosomes Are Protein-Synthesizing Machines

The Amyloid Precursor Protein Gives Rise to the β-Amyloid Peptide

Nonstandard Base Pairing Often Occurs Between Codons and Anticodons

The Folded Structure of tRNA Promotes Its Decoding Functions

Messenger RNA Carries Information from DNA in a Three-Letter Genetic Code

Transcription of Protein-Coding Genes and Formation of Functional mRNA

DNA Can Undergo Reversible Strand Separation

Native DNA Is a Double Helix of Complementary Antiparallel Strands