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E Pelosi

Publications and source records attributed to E Pelosi.

At least 19 recordsLinked to original sources
PubMed2006

The role of 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) in the management of patients with colorectal cancer.

AIM: In patients with colorectal cancer an accurate diagnostic work-up is mandatory in order to perform the most specific treatment. At this moment 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) is considered an accurate imaging technique in staging/restaging several malignancies. The aim of this paper is to review the scientific literature available about the role of FDG-PET in the management of patients with colorectal cancer. METHODS: An overview on Medline of scientific literature concerning FDG-PET and colorectal cancer was performed. The most relevant studies are reported. Advantages, limitations and new chances in using FDG-PET in these subsets of patients are summarized. RESULTS: FDG-PET is a useful tool in the evaluation of colorectal cancer. In comparison to conventional imaging technique, FDG-PET has an additional diagnostic value because it allows to metabolically characterize undetermined lesions suspected for recurrence of disease, to perform a complete pre-surgical staging and to identify occult metastatic disease. In clinical practice its use leads to a change in therapeutic choices in a high percentage of cases. CONCLUSIONS: FDG-PET should be considered an essential diagnostic tool in the management of patients with colorectal cancer, especially in recurrent disease evaluation.

Colorectal Neoplasms↗
PubMed2006

Identification of a molecular signature for leukemic promyelocytes and their normal counterparts: Focus on DNA repair genes.

Acute promyelocytic leukemia (APL) is a clonal expansion of hematopoietic precursors blocked at the promyelocytic stage. Gene expression profiles of APL cells obtained from 16 patients were compared to eight samples of CD34+-derived normal promyelocytes. Malignant promyelocytes showed widespread changes in transcription in comparison to their normal counterpart and 1020 differentially expressed genes were identified. Discriminating genes include transcriptional regulators (FOS, JUN and HOX genes) and genes involved in cell cycle and DNA repair. The strong upregulation in APL of some transcripts (FLT3, CD33, CD44 and HGF) was also confirmed at protein level. Interestingly, a trend toward a transcriptional repression of genes involved in different DNA repair pathways was found in APL and confirmed by real-time polymerase chain reactor (PCR) in a new set of nine APLs. Our results suggest that both inefficient base excision repair and recombinational repair might play a role in APLs development. To investigate the expression pathways underlying the development of APL occurring as a second malignancy (sAPL), we included in our study eight cases of sAPL. Although both secondary and de novo APL were characterized by a strong homogeneity in expression profiling, we identified a small set of differentially expressed genes that discriminate sAPL from de novo cases.

Adult↗
PubMed2006

Circulating haemopoietic and endothelial progenitor cells are decreased in COPD.

Circulating CD34+ cells are haemopoietic progenitors that may play a role in tissue repair. No data are available on circulating progenitors in chronic obstructive pulmonary disease (COPD). Circulating CD34+ cells were studied in 18 patients with moderate-to-severe COPD (age: mean+/-sd 68+/-8 yrs; forced expiratory volume in one second: 48+/-12% predicted) and 12 controls, at rest and after endurance exercise. Plasma concentrations of haematopoietic growth factors (FMS-like tyrosine kinase 3 (Flt3) ligand, kit ligand), markers of hypoxia (vascular endothelial growth factor (VEGF)) and stimulators of angiogenesis (VEGF, hepatocyte growth factor (HGF)) and markers of systemic inflammation (tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8) were measured. Compared with the controls, the COPD patients showed a three-fold reduction in CD34+ cell counts (3.3+/-2.5 versus 10.3+/-4.2 cells.microL-1), and a 50% decrease in AC133+ cells. In the COPD patients, progenitor-derived haemopoietic and endothelial cell colonies were reduced by 30-50%. However, four COPD patients showed progenitor counts in the normal range associated with lower TNF-alpha levels. In the entire sample, CD34+ cell counts correlated with exercise capacity and severity of airflow obstruction. After endurance exercise, progenitor counts were unchanged, while plasma Flt3 ligand and VEGF only increased in the COPD patients. Plasma HGF levels were higher in the COPD patients compared with the controls and correlated inversely with the number of progenitor-derived colonies. In conclusion, circulating CD34+ cells and endothelial progenitors were decreased in chronic obstructive pulmonary disease patients and could be correlated with disease severity.

Aged↗
PubMed2006

Role of whole body positron emission tomography/computed tomography scan with 18F-fluorodeoxyglucose in patients with biopsy proven tumor metastases from unknown primary site.

AIM: The aim of this study was to evaluate the role of whole body PET/CT scan with (18)F-fluorodeoxyglucose (FDG) in the detection of the primary tumor in patients with metastatic cancer from unknown primary origin (CUP syndrome). METHODS: Sixty-eight consecutive patients, with CUP syndrome (39 lymph nodes, 29 visceral biopsy proven tumor metastases), underwent a whole-body FDG-PET/CT study. All enrolled patients were unsuccessfully studied, within the previous month, with physical examination, laboratory tests and conventional diagnostic procedures. All the pathological findings identified at PET/CT scan and suspected for primaries, were further investigated. After PET study, the minimum follow-up period for the inclusion in the studied population was 3 months. RESULTS: The primary tumor site was correctly identified by FDG-PET/CT in 24 patients (24/68, 35.3%): lung (n=9), rino/oro-pharynx (n=6), pancreas (n=5), colon (n=2), uterus (n=2). In 5 cases, FDG-PET scan did not identify a primary pathological focus, which was subsequently detected by other diagnostic methods within 3 months. In 39 patients (39/68, 57.4%), the primary tumor site was not localized. However, in 9 of them, FDG-PET/CT scan identified further unexpected metastases, modifying the stage of disease. Overall, the following oncological treatment was influenced by the PET scan, in a total of 33 patients (33/68, 48.5%). CONCLUSIONS: Our data strongly support the diagnostic contribution of whole body FDG-PET/CT scan in the evaluation of patients with CUP syndrome and suggest its use in an early phase of the diagnostic iter to optimize patient management.

Adult↗
PubMed2004

Impaired myelopoiesis in mice devoid of interferon regulatory factor 1.

Interferon regulatory factor (IRF)-1 is a transcription factor controlling the expression of several genes, which are differentially induced depending on the cell type and signal. IRF-1 modulates multiple functions, including regulation of immune responses and host defence, cell growth, cytokine signalling and hematopoietic development. Here, we investigated the role of IRF-1 in granulocytic differentiation in mice with a null mutation in the IRF-1 gene. We show that IRF-1(-/-) bone marrow cells exhibit an increased number of immature granulocytic precursors, associated with a decreased number of mature granulocytic elements as compared to normal mice, suggestive of a defective maturation process. Clonogenetic analyses revealed a reduced number of CFU-G, CFU-M and CFU-GM colonies in IRF-1(-/-) mice, while the number of BFU-E/CFU-E colonies was unchanged. At the molecular level, the expression of CAAT-enhancer-binding protein (C/EBP)-epsilon, -alpha and PU.1 was substantially lower in the CD11b(+) cells from the bone marrow of IRF-1(-/-) mice as compared to cells from wild-type mice. These results, together with the fact that IRF-1 is markedly induced early during granulo-monocytic differentiation of CD34+ cells, highlight the pivotal role of IRF-1 in the early phases of myelopoiesis.

Animals↗
PubMed2004

PET/CT in diagnostic oncology.

In the last years positron emission tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) has become an established technique for the staging and follow-up of a wide variety of neoplasms. As PET imaging is based on the physiological mediated distribution of the administered tracer, rather than on anatomic and structural characteristics of tissue, the addition of CT imaging to PET improves the interpretation of PET images. Recently, integrated PET/CT scanners have been developed that can produce directly functional PET and anatomical CT data 1 session, without moving the patient and with minimal delay between the reconstruction and fusion of the 2 image data sets. In addition, CT images are also being used for attenuation correction in the reconstruction process of the PET emission data. A brief review of the most relevant technical characteristics of 3 PET/CT systems, which represent the state of the art of this technology, are described. Furthermore an overview of PET/CT acquisition protocols and clinical applications of PET/CT in oncology are described. Overall, advantages of PET/CT over PET that may influence the clinical routine, have been identified as a) the shorter image acquisition time with benefit on patients throughput and on patient compliance, b) the better accuracy in anatomically localizing focal areas of abnormal tracer uptake and defining tumor extent and c) the possibility to stage a disease in 1 single step.

Fluorodeoxyglucose F18↗
PubMed2003

Control of erythroid cell production via caspase-mediated cleavage of transcription factor SCL/Tal-1.

SCL/Tal-1 is a helix-loop-helix (HLH) transcription factor required for blood cell development, whose abnormal expression is responsible for induction of T-cell acute lymphoblastic leukemia. We show here that SCL/Tal-1 is a key target of caspases in developing erythroblasts. SCL/Tal-1 degradation occurred rapidly after caspase activation and preceded the cleavage of the major erythroid transcription factor GATA-1. Expression of a caspase-resistant SCL/Tal-1 in erythroid progenitors was able to prevent amplification of caspase activation, GATA-1 degradation and impaired erythropoiesis induced by growth factor deprivation or death receptor triggering. The potent proerythropoietic activity of uncleavable SCL/Tal-1 was clearly evident in the absence of erythropoietin, a condition that did not allow survival of normal erythroid cells or expansion of erythroblasts expressing caspase-resistant GATA-1. In the absence of erythropoietin, cells expressing caspase-resistant SCL/Tal-1 maintain high levels of Bcl-X(L), which inhibits amplification of the caspase cascade and mediates protection from apoptosis. Thus, SCL/TAL-1 is a survival factor for erythroid cells, whereas caspase-mediated cleavage of SCL/Tal-1 results in amplification of caspase activation, GATA-1 degradation and impaired erythropoiesis.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Lymphatic mapping in early stage breast cancer: comparison between periareolar and subdermal injection.

The combination of preoperative lymphatic mapping with intra-operative probe detection is becoming the standard procedure for identifying tumour lymphatic spread at the time of initial treatment in breast cancer. There are a number of identification techniques for sentinel lymph nodes, but the concordance of the results of a sentinel lymph node biopsy with axillary lymph node dissection did not vary significantly among them. Periareolar (p.a.) injection of tracer is a new procedure specifically studied to overcome some limitations of other techniques; in two groups of patients with early breast cancer we compared the periareolar with the subdermal technique. One hundred and fifty biopsy proven breast cancer patients were consecutively enrolled in this study. This population was divided into two groups: (1) group A, including 100 cancers; lymphatic mapping was performed by s.d. injection of both blue dye and radiotracer; and (2) group B, including 50 cancers; lymphatic mapping was performed with a combination of blue dye injected p.a. and radiotracer injected s.d. For group A, with both techniques we identified one or more SLNs in 100/100 tumours; blue dye detected the SLNs in 99/100 cancers (99%), lymphoscintigraphy in 93/100 cancers (93%). The concordance rate was 92%. For group B, with both techniques we identified one or more SLNs in 49/50 cancers (98%); blue dye detected the SLNs in 48/50, lymphoscintigraphy in 46/50 cancers (92%). The concordance rate was 92%. In the present study p.a. and s.d. injection of blue dye give similar and comparable results. The periareolar technique is simpler and has several advantages over the subdermal technique.

Administration, Cutaneous↗
PubMed2003

Pre-operative lymphatic mapping and intra-operative sentinel lymph node detection in early stage endometrial cancer.

Lymphatic mapping and sentinel lymph node (SLN) biopsy are becoming increasingly useful for the identification of tumour lymphatic spread in a wide variety of neoplasms, such as breast cancer and melanoma, reducing unnecessary radical lymph node resection. The aim of our study was to determine the feasibility of lymphatic mapping with both labelled colloid and patent blue violet in patients with early stage endometrial cancer. Sixteen consecutive patients with endometrial cancer, stage International Federation of Gynecology and Obstetrics (FIGO Ib), were included in the study. Lymphoscintigraphy and laparoscopically assisted intra-operative SLN detection were performed in all patients. In addition, to verify the prognostic role of this method, 12 of 16 patients were followed up for a period of at least 1 year. In 15 of 16 patients, 24 SLNs (all internal iliac lymph nodes) were detected at lymphoscintigraphy (six monolateral and nine bilateral). At histological analysis, three of the 24 were positive for micrometastases, whereas the remaining 21 were negative. No other surgically dissected lymph nodes presented metastases. At 1 year of follow-up, none of the 12 patients presented relapse of their disease. In conclusion, in endometrial cancer, both pre-operative lymphoscintigraphy and intra-operative gamma-probe detection of SLNs represent promising tools for the visualization of SLNs. The status of the latter may yield a correct representation of pelvic lymph node involvement, providing important information for further treatment.

Adenocarcinoma↗
PubMed2002

Prognosis of hibernating myocardium is independent of recovery of function: evidence from a routine based follow-up study.

Revascularization of hibernating segments improves both ventricular function (VF) and survival. In this study, we determined whether this relation is true in a routine based patients population with mildly reduced VF. Two to 6 years after undergoing 201Tl scintigraphy to detect hibernation, 153 patients were interviewed in order to collect medical information. This population was divided into four groups, according to the presence or absence of myocardial hibernation and of revascularization. Age, gender and left ventricular ejection fraction (LVEF) were similar in the four groups. Hard cardiac events (HEs) were noted in 14/33 (41%) patients with uncorrected hibernation, while in the other three groups HEs were recorded in fewer than 3% of patients. Univariate analysis indicated that the presence of hibernation, regardless of its extension, was the highest significant predictor of HEs. Multivariate analysis indicated that hibernation, stress ischaemia, age and absence of revascularization were significant predictors of HEs. These findings were not related to changes in LVEF or to New York Heart Association (NYHA) class during follow-up. In this routine based patient population, with mildly reduced VF, the rate of HEs seems to be related to uncorrected hibernation regardless of its extension. In these patients revascularization of hibernating segments is effective in reducing the risk of HEs while its role in improving VF or NYHA class is negligible.

Adult↗
PubMed2001

Endometriosis: absence of recurrence in patients after endometrial ablation.

BACKGROUND: The present study was undertaken to evaluate differences between patients with and without eutopic endometrium in the recurrence of ectopic endometriotic implants. METHODS: Endometrial ablation (EA) was carried out in 14 women out of 28 laparoscopically treated for endometriosis and recurrence of the disease was evaluated 24 months later. Data were compared using paired Student's t-test and chi2 test. RESULTS: Patients undergoing EA procedures did not exhibit recurrence of endometriosis while nine patients without that procedure had recurrence of the disease (P < 0.001). The endometrial cells found in the debris of the cul de sac of eight patients who did not undergo EA were both stromal and epithelial cells. No blood or blood cells were found in the cul de sac of patients undergoing EA. CONCLUSIONS: The present study supports a role of eutopic endometrium in the recurrence of endometriosis through tubal dissemination of endometrial debris and implantation of endometrial cells into the abdomen.

Adult↗
PubMed2000

PML/RAR alpha fusion protein expression in normal human hematopoietic progenitors dictates myeloid commitment and the promyelocytic phenotype.

The role of fusion proteins in acute myeloid leukemia (AML) is well recognized, but the leukemic target cell and the cellular mechanisms generating the AML phenotype are essentially unknown. To address this issue, an in vitro model to study the biologic activity of leukemogenic proteins was established. Highly purified human hematopoietic progenitor cells/stem cells (HPC/HSC) in bulk cells or single cells are transduced with retroviral vectors carrying cDNA of the fusion protein and the green fluorescent protein (GFP), purified to homogeneity and induced into multilineage or unilineage differentiation by specific hematopoietic growth factor (HGF) combinations. Expression of PML/RAR alpha fusion protein in human HPC/HSC dictates the acute promyelocytic leukemia (APL) phenotype, largely through these previously unreported effects: rapid induction of HPC/HSC differentiation to the promyelocytic stage, followed by maturation arrest, which is abolished by retinoic acid; reprogramming of HPC commitment to preferential granulopoietic differentiation, irrespective of the HGF stimulus (transduction of single sibling HPC formally demonstrated this effect); HPC protection from apoptosis induced by HGF deprivation. A PML/RAR alpha mutated in the co-repressor N-CoR/histone deacetylase binding region lost these biologic effects, showing that PML/RAR alpha alters the early hematopoietic program through N-CoR-dependent target gene repression mechanisms. These observations identify the cellular mechanism underlying development of the APL phenotype, showing that the fusion protein directly dictates the specific lineage and differentiation stage of leukemic cells. (Blood. 2000;96:1531-1537)

Acute Disease↗
PubMed2000

Hemoglobin switching in unicellular erythroid culture of sibling erythroid burst-forming units: kit ligand induces a dose-dependent fetal hemoglobin reactivation potentiated by sodium butyrate.

Mechanisms underlying fetal hemoglobin (HbF) reactivation in adult life have not been elucidated; particularly, the role of growth factors (GFs) is controversial. Interestingly, histone deacetylase (HD) inhibitors (sodium butyrate, NaB, trichostatin A, TSA) reactivate HbF. We developed a novel model system to investigate HbF reactivation: (1) single hematopoietic progenitor cells (HPCs) were seeded in serum-free unilineage erythroid culture; (2) the 4 daughter cells (erythroid burst-forming units, [BFU-Es]), endowed with equivalent proliferation/differentiation and HbF synthesis potential, were seeded in 4 unicellular erythroid cultures differentially treated with graded dosages of GFs and/or HD inhibitors; and (3) HbF levels were evaluated in terminal erythroblasts by assay of F cells and gamma-globin content (control levels, 2.4% and 1.8%, respectively, were close to physiologic values). HbF was moderately enhanced by interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor treatment (up to 5%-8% gamma-globin content), while sharply reactivated in a dose-dependent fashion by c-kit ligand (KL) and NaB (20%-23%). The stimulatory effects of KL on HbF production and erythroid cell proliferation were strictly correlated. A striking increase of HbF was induced by combined addition of KL and NaB or TSA (40%-43%). This positive interaction is seemingly mediated via different mechanisms: NaB and TSA may modify the chromatin structure of the beta-globin gene cluster; KL may activate the gamma-globin promoter via up-modulation of tal-1 and possibly FLKF transcription factors. These studies indicate that KL plays a key role in HbF reactivation in adult life. Furthermore, combined KL and NaB administration may be considered for sickle cell anemia and beta-thalassemia therapy.

Adult↗
PubMed2000

A diagnostic EIA for detection of the prevalent SRSV strain in United Kingdom outbreaks of gastroenteritis.

Small round structured viruses (SRSVs) are the major cause of outbreaks of gastroenteritis in the UK. Diagnosis is problematic due to insensitive electron microscopy (EM) or technically demanding reverse transcription polymerase chain reaction (RT-PCR) techniques. We have studied outbreaks of non-bacterial gastroenteritis using an EIA based upon recombinant capsid protein from the currently prevalent circulating strain of SRSV (Lordsdale Genotype II) and compared its performance against EM and RT-PCR assays. Faecal specimens sent to the Bristol Public Health Laboratory for outbreak investigation from December 1996 to December 1997 were applied retrospectively to the SRSV EIA and results compared with the routine EM and RT-PCR that had been carried out prospectively. Overall, the three tests identified SRSVs in specimens from 70% of the outbreaks (213/305) investigated. Of the 213 total positive outbreaks, the EIA identified 71%, that compared favourably with EM (63%) and RT-PCR (84%). The Lordsdale Genotype II SRSV EIA provides a simple cost-effective assay that will for the first time make detection of currently circulating SRSV strains associated with UK outbreaks available to all routine laboratories. The EIA format makes the assay widely applicable to non-specialist laboratories, unlike the RT-PCR assay, and the improved sensitivity over EM will allow successful screening of UK outbreaks alongside commercial EIAs currently available for adenovirus, astrovirus and rotavirus. Furthermore, the assay will allow rapid identification of emerging SRSV strains.

Capsid↗
PubMed2000

Technetium-99m labelled macroaggregated albumin arterial catheter perfusion scintigraphy: prediction of gastrointestinal toxicity in hepatic arterial chemotherapy.

Gastrointestinal toxicity from hepatic arterial infusion (HAI) of floxuridine in patients with liver metastases is probably due to extrahepatic perfusion or to partial escape of the drug from first-pass liver extraction. The aim of this study was to verify the role of technetium-99m-labelled macroaggregated albumin (99mTc-MAA) arterial catheter perfusion scintigraphy at the beginning of each chemotherapy cycle in decreasing or preventing gastrointestinal toxicity. We studied 167 consecutive patients. On the basis of the scintigraphic follow-up and the presence or absence of an intrahepatic arteriovenous shunt (IHAVS), we classified our patients into the following groups: (1) FU+ hepatic distribution pattern (DP), comprising 29 patients with regular scintigraphic follow-up who showed the expected distribution pattern at each control or a distribution pattern with transient alterations (extrahepatic escape) promptly reversed by the replacement of the catheter. Among these 29 patients there was one case of gastrointestinal toxicity. (2) FU- hepatic DP, comprising 128 patients who were evaluated with 99mTc-MAA only at the beginning of the first chemotherapy cycle, showed the expected distribution pattern and underwent HAI with no further scintigraphic evaluation. Among these 128 patients there were 28 cases of gastrointestinal toxicity. (3) FU+ pulmonary DP, comprising three patients with abnormally elevated pulmonary uptake (higher than 5%) and with regular scintigraphic follow-up. There were two cases of gastrointestinal toxicity among these three patients. (4) FU- pulmonary DP, comprising seven patients with abnormally elevated pulmonary uptake and without regular scintigraphic follow-up. There were four cases of gastrointestinal toxicity among these seven patients. The incidence of toxicity was significantly higher in group FU- hepatic DP than in group FU+ hepatic DP (21.9% vs 3.4%, P<0.05). In both the FU+ pulmonary DP and FU- pulmonary DP groups, the incidence of gastrointestinal toxicity was higher than 50%, with no significant difference between them. We conclude that, when performing 99mTc-MAA perfusion scintigraphy, the presence of an abnormally elevated pulmonary uptake (IHAVS higher than 5%) is the most relevant positive prognostic index for the development of gastrointestinal toxicity. Furthermore, in the absence of abnormal pulmonary uptake (IHAVS lower than 5%), strict scintigraphic follow-up is useful since it is able to promptly diagnose the presence of extrahepatic abdominal perfusion and thus to prevent the occurrence of gastrointestinal toxicity.

Adult↗
PubMed2000

Expression of interleukin 3 and granulocyte-macrophage colony-stimulating factor receptor common chain betac, betaIT in normal haematopoiesis: lineage specificity and proliferation-independent induction.

Interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 5 (IL-5) exert their biological activities through interaction with cell-surface receptors that consist of two subunits, a specific alpha subunit and a common beta transducing subunit (betac). We have evaluated the expression of betac on purified haematopoietic progenitor cells (HPCs) induced to unilineage differentiation/maturation through the erythroid (E), granulocytic (G), megakaryocytic (Mk) or monocytic (Mo) lineage. HPCs displayed low betac expression, which increased during the initial stages of HPC differentiation along the E, G, Mo or Mk lineages. At later stages of differentiation, betac chain expression increased in both G and Mo lineages, was expressed at low levels in the Mk lineage and declined to undetectable levels in the E lineage. Analysis of the full-length betac and intracytoplasmically truncated betac (betaIT) mRNAs showed that the former was predominant in the G and Mo lineages, whereas the latter was prevalent in the E and Mk lineages. The betac induction takes place even in the absence of cell cycling. Thus, incubation of HPCs with graded amounts of IL-3 showed that the initial induction of betac expression is unrelated to cell proliferation. Furthermore, circulating monocytes and granulocytes exhibit a low level of betac expression that is greatly stimulated following incubation with either IL-3 or GM-CSF.

Blotting, Western↗
PubMed2000

Mechanisms of differential transferrin receptor expression in normal hematopoiesis.

We have investigated the expression of transferrin receptor (TfR) iron regulatory protein-1 (IRP-1) and iron regulatory protein-2 (IRP-2) in liquid suspension culture of purified hematopoietic progenitor cells (HPCs) induced by a growth factor stimulus to proliferation and unilineage differentiation/maturation through the erythroid, granulocytic, monocytic and megakaryocytic lineages. In initial HPC differentiation, TfR expression is induced in both erythroid and granulopoietic cultures. In late HPC differentiation (i.e. starting from day 5 of culture) and then differentiated precursor maturation, the TfR gene is highly expressed in the erythroid lineage, whereas it is sharply downmodulated in the granulopoietic, monocytopoietic and megakaryocytic series. The elevated TfR expression in erythroid cells is: (a) mediated through a high rate of TfR gene transcription; (b) modulated by intracellular iron levels; (c) mediated by TfR mRNA stabilization through the iron regulatory protein (IRP), in that IRP-1 activity is high in erythroid lineage as compared to the levels observed in other hemopoietic lineages; and (d) dependent on exogenous erythropoietin (Epo) (this is indicated by the marked TfR and IRP-1/IRP-2 downmodulation after Epo starvation). Interestingly, analysis of IRP-1 and IRP-2 expression during hemopoietic differentiation showed that: (a) IRP-1 expression was maintained during all steps of erythroid differentiation, while it was lost in the other hemopoietic lineages; (b) IRP-2 expression was observed during all stages of hemopoietic differentiation in all four lineages. However, IRP-1 and IRP-2 expression and activity are induced when monocytes, which express only low levels of IRP-1 and IRP-2, are induced to maturation to macrophages. These studies indicate that: (a) in normal erythropoiesis, the hyperexpression of TfR, starting from early erythroid HPC differentiation, is Epo-dependent and mediated via transcriptional and post-transcriptional mechanisms; (b) in the granulopoietic, monocytopoietic and megakaryocytic pathways, the TfR is first induced and then downmodulated (the latter phenomenon is mediated via transcriptional suppression of the TfR gene and IRP inactivation).

Adult↗