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ABSTRACT: Myelodysplastic syndromes (MDS) are very heterogeneous diseases in terms of clinical presentation and prognosis. Patients with pure red cell dysplasias have a life expectancy of more than 10 years, whereas those with refractory anemias with excess blasts have survival shorter than 6 months. Until a few years ago, therapeutic options were palliative and supportive care only. Quite recently, the treatment panorama for MDS has radically changed and the different biological behavior of MDS requires a precise choice among completely different therapies: immunosuppressive agents, anti-apoptotic agents and growth factors are effective in low risk MDS, whereas epigenetic drugs, tyrosine kinase inhibitors, and possibly high dose chemotherapy and bone marrow transplantation are valuable in high risk MDS. We review the results of such therapies and the selection criteria for MDS patients.
Journal of chemotherapy (Florence, Italy) 07/2008; 20(3):291-6. · 1.08 Impact Factor
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ABSTRACT: We analysed the in vitro effects of a new hydroxamate derivative, ITF2357, on AML cells. ITF2357 potently induced histone acetylation. ITF2357 0.1 microM blocked proliferation and induced apoptosis in AML1/ETO-positive Kasumi-1 cells, while AML1/ETO-negative HL60, THP1 and NB4 cell lines were sensitive only to 1 microM ITF2357. Apoptosis was induced by 0.1 microM ITF2357 in AML1/ETO-positive primary blasts and U937-A/E cells induced to express AML1/ETO, but not in U937-A/E cells non-expressing AML1/ETO. In Kasumi-1 cells 0.1 microM ITF2357 induced AML1/ETO degradation through a caspase-dependent mechanism. ITF2357 0.1 microM also determined DNMT1 efflux from, and p300 influx to, the nucleus. Moreover, 0.1 microM ITF2357 determined local H4 acetylation and release of DNMT1, HDAC1 and AML1/ETO, paralleled by recruitment of p300 to the IL-3 gene promoter. ITF2357 treatment, however, did not induce re-expression of IL-3 gene. Accordingly, the methylation level of IL-3 promoter, as well as of several other genes, was unmodified. In conclusion, ITF2357 emerged as an anti-leukaemic agent very potent on AML cells, and on AML1/ETO-positive cells in particular. More relevantly, clearly emerged from our results that ITF2357 could be an ideal agent to treat AML subtypes presenting AML1/ETO fusion protein which determine HDAC involvement in leukaemogenesis.
Oncogene 04/2008; 27(12):1767-78. · 6.37 Impact Factor
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ABSTRACT: Epigenetic modifications are reversible chromatin rearrangements that in normal cells modulate gene expression, without changing DNA sequence. Alterations of this equilibrium, mainly affecting the two interdependent mechanisms of DNA methylation and histone acetylation, are frequently involved in the genesis of cancer. The histone code, regulating gene expression, is constituted by the combination of different acetylated lysine residues of histones. In neoplastic cells, the abundance of deacetylated histones is usually associated with DNA hypermethylation and gene silencing. Several compounds, known to have in vitro antineoplastic activity, have been eventually shown to act as histone deacetylase inhibitors. Thus, HDAC inhibitors have been successfully introduced in clinical trials as antitumour agents. They are classified according to their chemical structures and are endowed with different specificity and affinity for the HDACs of classes 1, 2, 4. Among HDAC inhibitors, the most potent are the hydroxamic acid derivatives, like SAHA, which has been recently approved for therapy of cutaneous T-cell lymphomas. Other classes of HDAC inhibitors are short chain fatty acids (SCFA), benzamides, epoxyketone and non-epoxyketone containing cyclic tetrapeptides, and hybrid molecules. SCFA, although widely used (especially valproic acid) and clinically efficacious, have weak HDAC inhibition constants. Benzamides, like MS-275, and cyclic peptides, like depsipeptide, have been studied in numerous clinical trials and demonstrated low toxicity and activity in solid and haematological neoplasms. HDAC inhibitors are also potent radiation sensitizers. Their future in oncology may thus be based on their activity as single agents and on their synergy with the hypomethylating drugs and with chemo- and radiotherapeutics.
Current Drug Metabolism 06/2007; 8(4):383-93. · 5.11 Impact Factor
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ABSTRACT: Cephalotoxine esters, including homoharringtonine (HHT), have shown encouraging activity in leukemia in initial studies in China and in later studies in the U.S.
The authors conducted a review of the literature to examine the studies pertinent to HHT in relation to preclinical studies and Phase I-II trials in patients with hematologic malignancies and solid tumors.
HHT and analogues appear to induce differentiation and apoptosis. Studies from China reported high response rates in patients with leukemia. Trials in the U.S. using short HHT infusions (3-4 mg/m(2) daily for 5 days) resulted in a high incidence of cardiovascular complications that were reduced using continuous infusion schedules of 3-7 mg/m(2) daily for 5-7 days initially, and later lower dose schedules of 2.5 mg/m(2) daily for 7-14 days. Results in solid tumors were negative. However encouraging results were reported in patients with acute myeloid leukemia, myelodysplastic syndrome, acute promyelocytic leukemia, and, most important, chronic myeloid leukemia (CML). In CML patients, HHT has been investigated alone and in combination with interferon-alpha and low-dose cytarabine in late and early chronic phases, with positive results. Additional areas of interest include the potential use of HHT for the treatment of central nervous system leukemia, polycythemia vera, and other nonmalignant conditions such as malaria. New semisynthetic preparations and HHT derivatives that bypass multidrug resistance may improve the efficacy and toxicity profiles, and broaden the range of antitumor efficacy.
HHT and its derivatives appear to have promising activity in hematologic malignancies, a finding that needs to be pursued.
Cancer 10/2001; 92(6):1591-605. · 4.77 Impact Factor
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ABSTRACT: n-Butyric acid and its "polymorphic" derivatives have been largely but somehow "blindly" studied in oncology and in red cell diseases with consistent results through decades indicating a strong maturative effect determined by enhancement of gene transcription. Although these effects have been observed mainly in vitro, the relative absence of systemic toxicity of butyrates render these compounds appealing as specific therapeutic agents. More interestingly, their specific mechanism of action, i.e. inhibition of histone deacetylase and de-repression of transcription represents at present an unique tool for diseases such as acute leukemias which are characterised by a disregulation of co-repressors and co-activators of gene transcription. More insight into specificity and modalities of action of different butyrate derivatives may be a guarantee for excellent tailored antileukemic therapy in the future.
Leukemia and Lymphoma 08/2001; 42(3):275-89. · 2.58 Impact Factor
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ABSTRACT: Methylation of DNA is a biochemical modification that can influence gene expression and is involved in inactivating one of the two X chromosomes in women. Evidence that has accumulated in the past 10 years suggests that cancer cells usurp this physiologic mechanism and use it to their benefit by inactivating tumor suppressor genes and related proteins. However, the primary structure of the affected proteins remains intact; reversal of abnormalities in DNA methylation may therefore restore the tumor-suppressive function of these genes and provide a novel approach to cancer therapy. Two demethylating drugs, 5-azacytidine and 5-aza-deoxycytidine, are currently being tested in clinical trials, and several others are in preclinical development. In this article, the biological rationale for targeting aberrant methylation in cancer therapy is reviewed and completed phase I and II trials of this approach, some of which show promise for treatment of hematologic malignancies, are summarized.
Annals of internal medicine 05/2001; 134(7):573-86. · 16.73 Impact Factor
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V Santini
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ABSTRACT: Amifostine (Ethyoltrade mark, Alza Pharmaceuticals) is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[3- aminopropyl)amino]dihydrogen phosphate. It is a prodrug of free thiol (WR-1065) that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. Differences in the alkaline phosphatase concentration of normal versus tumour tissues can result in greater conversion of amifostine in normal tissues. Inside the cell, WR-1065 provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapy agents. Preclinical animal studies have demonstrated that the administration of amifostine protects against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine has been shown to protect a variety of animal species from lethal doses of radiation. Amifostine gives haematological protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin and salivary gland protection from radiotherapy. Multiple Phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine were found to be 740 - 910 mg/m(2) in single-dose regimens and 340 mg/m(2) in multiple-dose regimens. In radioprotection, doses are generally 200 - 350 mg/m(2). For all these characteristics, amifostine has been recently approved and suggested in ASCO clinical practice guidelines as a radioprotector for head and neck cancer treatment and supportive agent during cisplatin-based chemotherapy, in lymphomas and solid tumours. Moreover, its spectrum of possible applications is enlarging. As data have been provided indicating that amifostine stimulates haematopoiesis, it has been employed with intriguing results in the treatment of myelodysplastic syndromes (MDS).
Expert Opinion on Pharmacotherapy 04/2001; 2(3):479-89. · 3.20 Impact Factor
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Haematologica 02/2001; 86(1):104. · 6.42 Impact Factor
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ABSTRACT: The phosphorylated aminothiol agent amifostine (Ethyol) protects bone marrow and other tissues from toxicity due to ionizing radiation and antineoplastic drugs, and stimulates progenitors from normal and myelodysplastic bone marrow. Contrasting results have been published so far on the effectiveness of amifostine in correcting cytopenia in patients with myelodysplastic syndromes (MDS).
In a pilot phase II study we treated 26 patients with low risk MDS (13 RA, 2 RARS, 2 CMML, 9 RAEB with blasts < 10%) with amifostine (200 mg/m(2 )x 3/week for 4 weeks).
Hemoglobin concentration, reticulocyte, neutrophil and platelet counts increased respectively in 6 (23%), 11 (42%), 13 (50%) and 9 (34%) of patients. Red cell transfusions were reduced (> 50%) in 4/26 patients and abolished in 1/26. Unexpectedly a significant decrease in soluble transferrin receptor level at week 4 of therapy, compared to the basal level (p<0.04), was observed in the whole population of patients.
Amifostine can ameliorate cytopenia in some patients with MDS, with few and mild side effects. Neutropenia is more likely to be corrected than anemia or thrombocytopenia. Mechanisms underlying this biological effect remain to be clarified.
Haematologica 04/2000; 85(4):367-71. · 6.42 Impact Factor
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ABSTRACT: Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100 mg/m2 continuous intravenous (i.v.) infusion over 4 days, fluda 30 mg/m2 i.v. over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m2 i.v. over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage I-II patients had a median survival of 7 months and stage III-IV patients had a median survival of 3 months. Major toxicities (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent. In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-p/fluda combination in this study group.
Leukemia and Lymphoma 12/1999; 36(1-2):57-65. · 2.58 Impact Factor
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ABSTRACT: Different therapeutic approaches are needed to restore apoptotic mechanisms in CLL cells, as present ones are not successful. We assessed the apoptotic effects of stable butyrate derivatives on CLL lymphocytes: in these molecules a mannose molecule is bound as ester to one-five butyrate moieties, conferring pharmacological stability to the pro-drugs which are able to induce apoptosis in primary AML blasts.
Peripheral blood samples obtained from 17 patients with typical B-CLL were cultured in the presence of 0.5-1mM D1 (O-n-butanoyl-2, 3-O-isopropylidene-a-D-mannofuranoside), F1 (1-O-n-butanoyl-2, 3-O-isopropylidene-D,L-xylitol) and G1 (1-O-n-butanoyl-D,L-xylitol) derivatives for 4 days and equimolar sodium butyrate as comparison. After culture, apoptosis was evaluated by cell morphology, cellular DNA content, pattern of DNA fragmentation, annexin V exposure on cell membrane, and cell cycle parameters. Bcl2, bax, and fas oncogene expression were also evaluated by the APAAP method.
The addition to cell cultures of D1 or F1 or G1 butyrate monosaccharides as well as sodium butyrate 0.5 and 1 mM determined to different extents an increase in the percentage of apoptotic cells in all CLL samples, relatively to the method and butyrate molecule added in culture. Heterogeneity in CLL cell sensitivity to the three butyrates was observed. Up to 60-68% apoptotic bodies were present in treated cultures after exposure to D1 0.5-1 mM, 60-72% after F1 0.5-1 mM and 48-60% after G1 0.5-1 mM. Comparison of untreated versus treated cultures yielded important significance (p< 0.001). At DNA content analysis, analyzed by flow cytometry, apoptotic events were accounting for up to 70-77% of D1-treated and 68-74% of F1-treated CLL cells at 0.5 and 1 mM concentrations (p= 0. 0001, vs controls 0-39%), and for 72-81% of G1 (0.5-1 mM) treated cells (overall, p=0.005). Cell cycle parameters were not altered by addition of butyrates, but expression of Annexin V was greatly enhanced. In a limited number of CLL cases fas, bcl2/bax ratio was analyzed and found unmodified.
Monosaccharide butyrate stable derivatives are potent inducers of primary CLL cell apoptosis, both in untreated and alkylating agent pre-treated cases. Our results suggest that the apoptotic pathways elicited by butyrate in CLL lymphocytes are direct, specific and most probably do not involve bcl2/bax. Pro-apoptotic agents like the stable monosaccharide butyrate derivatives here studied could bring more insights into CLL biology and resistance to apoptosis, and possibly originate alternative treatments for CLL.
Haematologica 11/1999; 84(10):897-904. · 6.42 Impact Factor
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ABSTRACT: Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihydrogen phosphate. It is a pro-drug of free thiol that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs, and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. In fact, pretreatment with amifostine was well tolerated and reduced the cumulative hematologic, renal and neurological toxicity associated with cisplatin, cyclophosphamide and vinblastine therapy of advanced and metastatic solid tumors. The objective of this review is to focus the importance of amifostine as a myeloprotective and cytoprotective drug during treatment with chemotherapeutics, presenting the most recent results, and to discuss the application of amifostine in the therapy of myelodysplastic syndromes.
The material analyzed in this study includes data published or under publication by the authors as full papers or clinical protocols. Articles and abstracts published in Journals covered by Medline constitute the other source of information.
Amifostine, formerly known as WR-2721, is an organic thiophosphate that was developed to protect normal tissues selectively against the toxicities of chemotherapy and radiation. Amifostine is a pro-drug that is dephosphorylated at the tissue site to its active metabolite by alkaline phosphatase. Differences in the alkaline phosphatase concentrations of normal versus tumor tissues can result in greater conversion of amifostine in normal tissues. Once inside the cell the free thiol provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapies. Preclinical animal studies demonstrated that the administration of amifostine protected against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity, and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine was shown to protect a variety of animal species from lethal doses of radiation. Studies in tumor-bearing animals demonstrated that the administration of amifostine results in cytoprotection without loss of antitumor activity. Multiple phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine resulted to be 740-910 mg/m(2) in a single dose regimen, and 340 mg/m(2) in a multiple dose regimen. Amifostine afforded not only hematologic protection, but also other organ protection from cytotoxic agents such as nephrotoxicity, mucositis and peripheral neuropathy from cisplatin. Many studies have been performed to investigate cytoprotective efficacy of amifostine. In brief, amifostine gives hematologic protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin, and salivary gland from radiotherapy. In phase I/II studies these properties have been confirmed, together with a generally good tolerability of the drug, hypotension being the most common side effect. It has been observed that amifostine possibly enhances the anti-tumor effect of carboplatin, nitrogen mustard, melphalan, and cisplatin combined with 5-FU or vinblastine. For all these characteristics, amifostine is at present broadly used as supportive treatment during chemotherapy, in lymphomas and solid tumors, and its spec
Haematologica 11/1999; 84(11):1035-42. · 6.42 Impact Factor
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ABSTRACT: Tumor necrosis factor-a plays an important role in hematopoiesis. Its effects are mediated through two membrane-bound receptors: TNF-R I (p55; CD 120a) and TNF-R II (p75; CD 120b). The aim of our study was to investigate the relative roles of these receptors.
We analyzed in 16 acute myeloid leukemia cases whether TNF-alpha could induce in vitro maturation and apoptosis. We then investigated which of the two receptors was provoking monocytic maturation and which was responsible for apoptosis by using the agonistic MoAb HTR-9, directed at CD120a, and the CD120b antagonistic MoAb UTR-1.
Monocytic maturation (morphologic and immunologic) was induced in all cases studied, although to different rates, by TNF-alpha and by HTR-9 incubation. The addition of UTR-1 to TNF-alpha did not abolish maturation, nor did it affect apoptosis, which was present in primary AML cultures after 4 and 10 days.
We present here evidence that the sole stimulation of CD 120a, but not of CD120b, by TNF-alpha is responsible for bot monocytic maturation and apoptosis of primary AML blasts.
Haematologica 05/1999; 84(4):291-7. · 6.42 Impact Factor
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ABSTRACT: Gaucher's disease is frequently associated with immunologic abnormalities, e.g. hypergammaglobulinemia, polyclonal gammopathy and benign monoclonal gammopathy. A patient with Gaucher's disease and a selective accumulation of IgM k in Gaucher's cells without serum monoclonal gammopathies is described. The selective accumulation is detected by immunohistochemistry analysis performed on cryostat bone marrow biopsies.
European journal of histochemistry: EJH 02/1999; 43(3):235-9. · 1.69 Impact Factor
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Advances in experimental medicine and biology 02/1999; 457:89-94. · 1.09 Impact Factor
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P Pouillart,
O Douillet,
B Scappini,
A Gozzini, V Santini,
A Grossi,
G Pagliai,
P Strippoli,
L Rigacci,
G Ronco,
P Villa
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ABSTRACT: Regiospecific synthesis of 12 novel n-butyric and phenylalkylcarboxylic monoesters of mannose and xylitol was achieved. The strategy adopted, avoided a tedious intramolecular transesterification step, previously described for the synthesis of analogous compounds and permitted the facile synthesis of a new generation of stable derivatives. The general tolerance of the drugs has been assayed after intravenous administration of a bolus dose into mice. Monobutyric esters showed a low toxicity commensurate with the requirements for future development. A relationship was observed between chain length and toxicity. In contrast, phenylacetic, 3-phenylpropionic and 4-phenylbutyric esters were found to be toxic. Phenylbutyric esters induced marked and specific neuromuscular damage. Preliminary biological investigations of the new series of monobutyric esters showed them to retain the benificial biological properties of butyric acid whilst remaining relatively non toxic. They induced an inhibition of in vitro proliferation of 10 human cases of de novo acute myeloid leukemia (AML) primary cultures and AML established cell lines. AML blasts growth appeared to be blocked and cell differentiation was established. Transcription and expression of maturation markers and finally apoptosis were observed. Moreover, human gamma-chain hemoglobin (HbF) synthesis in erythroleukemia cells was stimulated by monobutyric esters. Mannose and xylitol butyric derivatives would appear to have exciting potential in treatment of beta-Hemoglobinopathies, sickle cell anemia and cancer.
European Journal of Pharmaceutical Sciences 02/1999; 7(2):93-106. · 3.21 Impact Factor
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ABSTRACT: Vinorelbine (VNR) is a new semi-synthetic Vinca rosea alkaloid that has been employed both in combination and as a single agent, showing a significant antitumour activity. Since little is known about VNR in human leukemia, we studied the in vitro cytotoxic effect of VNR on peripheral blood lymphocytes from 18 patients affected by B-chronic lymphocytic leukemia (CLL), employing the INT assay. VNR inhibited fresh B-CLL cells from 15/18 patients in primary cultures, the ID50 doses ranging from 4 ng/ml to 83 micrograms/ml. These data strongly suggest that VNR could be effective in the treatment of B-CLL.
Advances in experimental medicine and biology 02/1999; 457:473-6. · 1.09 Impact Factor
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ABSTRACT: We report the onset of pure red cell aplasia (PRCA) in a patient with a history of polyglandular syndrome including Addison's disease, malabsorption syndrome, diabetes type I and gastric hyperplastic polyposis. An autoimmune origin for this complex disorder was not supported by the presence of organ specific antibodies, but T cells were found to be of polyclonal origin, as demonstrated by molecular analysis of T cell receptor (TCR) gene rearrangement. The pathophysiology of this case, based on laboratory findings and response to therapy, is discussed.
Haematologica 12/1998; 83(11):1043-5. · 6.42 Impact Factor
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British Journal of Haematology 10/1998; 102(5):1124-38. · 4.94 Impact Factor
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ABSTRACT: There is evidence to suggest a close relationship between the erythroid and megakaryocytic lineages. Using RT-PCR, we evaluated the coexpression of erythroid and megakaryocytic genes in blasts from 25 acute myeloid leukaemia (AML) cases (FAB M1-M7) and three unclassifiable leukaemias with trilineage dysplasia (trilineal AML). All FAB M6 and M7 and trilineal leukaemias expressed mRNAs for alpha-globin, glycoprotein IIb (GpIIb), erythropoietin receptor (Epo-R) and thrombopoietin receptor (c-mpl), but not for myeloperoxidase (MPO) which in contrast was expressed in the other FAB-subtype leukaemias. These data support the hypothesis that blasts from M7 and M6 leukaemias may derive from (or represent) a common progenitor cell with resident bipotentiality towards the megakaryocytic and erythrocytic lineages.
British Journal of Haematology 10/1998; 102(5):1335-7. · 4.94 Impact Factor
