SEARCH · Search PubMed

Results for “THROMBOCYTOSIS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,459 records · Page 81Linked to original sources

PubMed2003

Sudden onset of the blastic phase of chronic myelogenous leukemia: patterns and implications.

BACKGROUND: Therapeutic options in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph-positive CML) in chronic phase include allogeneic stem cell transplantation (SCT) and treatments other than allogeneic SCT. The choice of therapy often depends on the mortality risk of allogeneic SCT. Delaying SCT until the disease demonstrates resistance to other strategies (e.g., imatinib mesylate or interferon-alpha) entails the risk of the development of a sudden blastic phase, which may not permit enough time to perform a SCT. METHODS: The current study was performed to define the incidence and patterns of sudden-onset blastic-phase CML in relation to the risk inherent in delaying allogeneic SCT. Of a study group of 1286 patients who were referred in early chronic-phase CML between 1981-2001 and who received therapies other than allogeneic SCT, 1093 patients had regular follow-up at the study institution. A sudden onset of blastic phase was defined as having its onset within 3 months from a previously documented complete hematologic response. RESULTS: Among the 1093 patients, 183 patients developed blastic-phase disease, which was of sudden onset in 46 patients (25%; 4% of the total). The incidence of sudden blastic phase was 0.4% in the first year, 1.8% in the second year, and 2.6% in the third year. Patients with sudden blastic-phase disease were found to have more often low-risk features at the time of presentation, including low incidences of blasts and thrombocytosis. Sudden blastic-phase CML was found to be associated with a higher incidence of lymphoid blastic morphology (67% vs. 22%; P < 0.0001), which resulted in a higher response rate to blastic-phase therapy (70% vs. 29%; P < 0.0001) and significantly longer survival from the onset of blastic-phase disease (median of 12 months vs. 6 months; P < 0.01). Twenty-four of the 42 patients with sudden blastic-phase disease who were treated at the M. D. Anderson Cancer Center were able to undergo allogeneic SCT in second chronic phrase (n = 13) or transformed phase (n = 11); at the time of last follow-up, 6 patients were alive without evidence of disease at a median of 18 months. CONCLUSIONS: The low rates of sudden blastic transformation in the first 3 years of the course of disease for CML and the salvage rate of these patients with allogeneic SCT should be considered in relation to the transplantation mortality in patients with early chronic-phase disease and the early promising results with imatinib mesylate therapy.

Adult↗

PubMed1992

Hematopoietic growth factors secreted by seven human pleural mesothelioma cell lines: interleukin-6 production as a common feature.

Seven mesothelioma cell lines, established from patients with pleural mesothelioma, exhibited substantial heterogeneity regarding in vitro morphology and growth characteristics. Media conditioned by these cell lines and by MeT5A normal mesothelial cells were examined for (i) colony formation on human bone-marrow cells, (ii) hematopoietic growth-factor content and (iii) mitogenic activity on mesothelioma cells. Colony-stimulating activity was produced only by the ZL34 cell line. Analysis of conditioned media by ELISA revealed that all mesothelioma cell lines constitutively produced IL-6, while the MeT5A normal mesothelial cells did not; in addition, GM-CSF and G-CSF were detected in the supernatant of the ZL34 cell line. Using a 3H-thymidine incorporation assay, we showed that all mesothelioma cell lines produced mitogenic activity in the culture supernatant, in contrast to the MeT5A normal mesothelial cells. The mitogenic effect of the hematopoietic growth factors detected in mesothelioma culture supernatants was tested on mesothelioma cells and on MeT5A normal mesothelial cells: IL-6, GM-CSF and G-CSF did not stimulate any DNA synthesis. Our results suggest that these hematopoietic growth factors do not act as autocrine growth factors. A common feature of this panel of mesothelioma cell lines is the production of IL-6; although the biological significance of the aberrant production of cytokines by mesotheliomas remains unclear, IL-6 might be involved in paraneoplastic syndromes such as thrombocytosis.

Granulocyte Colony-Stimulating Factor↗

PubMed1995

Manifestations of cancer cachexia induced by colon 26 adenocarcinoma are not fully ascribable to interleukin-6.

In order to further clarify the role of interleukin 6 (IL-6) in the pathogenesis of cachexia, recombinant human IL-6 (hIL-6) was administered s.c. by osmotic pump for 9 days at a dose of 1 or 10 micrograms/day into CDF1 mice inoculated with a non-cachexia-inducing subclone of colon 26 adenocarcinoma (clone 5), or with a cachexia-inducing subclone (clone 20) of this malignancy. The serum level of IL-6 in non-cachectic mice with clone-5 tumors was 35% lower than in cachectic mice bearing clone 20 of colon 26 adenocarcinoma on the 19th day after tumor inoculation. IL-6 administration induced anemia, thrombocytosis and visceral organ hypertrophy not only in mice with clone-5 tumors but also in control mice with no tumor burden. Lipolysis and proteolysis became conspicuous when a large dose (10 micrograms/day) of IL-6 was infused into mice with clone-5 tumors. However, IL-6 supplementation did not induce loss of body weight, a decline in food intake or lymphocytopenia, which were characteristically observed in cachectic mice with clone-20 tumors. In conclusion, IL-6 appears to be a permissive factor for the development of cachexia but, while it can induce some of the symptoms typical of cachexia, it cannot in itself induce the full cachectic syndrome.

Adenocarcinoma↗

PubMed1998

Inflammatory process complicating giant hemangioma of the liver: report of three cases.

Three cases of giant hemangioma of the liver associated with clinical and laboratory signs of inflammatory process, including low-grade fever, weight loss, abdominal pain, accelerated erythrocyte sedimentation rate, anemia, thrombocytosis, and increased fibrinogen level with normal white blood cell count are described. One patient presented with slight cholestatic jaundice because of tumor-related bile duct compression, but the other two patients had normal liver function tests, except for a slight increase in gammaglutamyl transferase. Clinical and laboratory abnormalities disappeared after surgical excision. Inflammatory manifestations have rarely been reported during giant liver hemangioma. Intratumoral inflammation necrosis or bleeding could explain the symptoms but histological signs of inflammation were not detected in two of three surgical specimens. The release of immune mediators by liver endothelial cells lining the hemangioma is an alternative explanation. The incidence of inflammatory process complicating giant hemangioma is probably underestimated because our three cases were observed within a span of only 3 years.

Adult↗

PubMed1978

Blastic transformation in chronic myelogenous leukemia: experience with 50 patients.

Fifty consecutive patients with blastic chronic myelogenous leukemia were evaluated clinically, morphologically, biochemically, and therapeutically. Forty-five patients had a preceding stable phase (38 Ph'+, 7 Ph'-); five patients presented with de novo Ph+ blast crisis. The most frequent clinical signs of impending blast crisis were weakness, fatigue, increasing splenomegaly, anemia, thrombocytopenia, marrow fibrosis, and a rising neutrophil alkaline phosphatase. Fever (unrelated to infection), skin infiltration, lymphadenopathy, hepatomegaly, thrombocytosis, and basophilia were much less common. The development of aneuploidy occurred in less than one-half of the total group. Myeloblastic morphology at blastic transformation was most frequent with occasional lymphoblastic, promyelocytic, and undifferentiated cases seen. Terminal deoxynucleotidyl transferase was present in one-third of the patients, but had no clear-cut relationship to the morphology. Response to treatment was generally disappointing (two complete and 15 partial remissions in 45 treated patients).

Adult↗

PubMed1988

Hematologic and clinical features of patients with chromosome 5 monosomy or deletion (5q).

This paper analyzes the hematologic features and outcome of 13 patients with chromosome 5 abnormalities (monosomy 5 or deletion of 5q), either isolated or with additional anomalies. Among four patients with isolated del (5q), two had a stable refractory macrocytic anemia with thrombocytosis (5q-syndrome). All nine patients with complex karyotypes had acute leukemia or refractory anemia with excess of blasts in acute transformation; two cases were TdT-positive, with a lymphoid or a mixed phenotype. In seven patients, preleukemia preceded overt leukemia, and in six, a prior therapeutic, or occupational exposure to mutagens/carcinogens had occurred. Additional chromosome 7 abnormalities were seen in four cases. The median survival of patients with complex karyotypes was 19 months from the time of diagnosis of the hematologic disorder and 5 months from the time of identification of the chromosome 5 abnormality. Pathogenetic implications of the chromosome 5 monosomy or del (5q) through a proto-oncogene activation and the putative hemopoietic stem cell involvement in a clonal disease are discussed.

Adult↗

PubMed2005

Normal thrombopoietin and its receptor (c-mpl) genes in children with essential thrombocythemia.

BACKGROUND: Following the observation of thrombopoietin (TPO) gene abnormalities as the cause of familiar cases of thrombocythemia similar derangements of TPO and/or its receptor (c-mpl) might be surmised to be at the root of increased platelet count also in non-familiar (sporadic) cases. Although this was not demonstrated in adults, little data exist about childhood. PROCEDURES: We studied the molecular biology of TPO and c-mpl in seven children with non-familiar essential thrombocythemia (ET) and one child with secondary thrombocytosis (ST). Plasma TPO content was measured using a commercially available kit. Genomic DNA was extracted from whole blood by standard methods and TPO and c-mpl genes were amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: Plasma TPO levels were normal in all our patients. No alteration was detected in either coding region, including the flanking intronic sequences of TPO and c-mpl genes. As compared to the published normal sequence of the TPO gene, one allelic base change in a non-coding region of intron 1 was found in all children with ET and ST, but this was reported as a common finding in normal subjects as well. CONCLUSIONS: High platelet count in our series of sporadic ET of childhood is not due to an abnormality either of TPO or c-mpl gene.

Adolescent↗

PubMed2005

Pediatric inflammatory myofibroblastic tumor: anaplastic lymphoma kinase (ALK) expression and prognosis.

BACKGROUND: Pediatric inflammatory myofibroblastic tumor (IMT) is rare, with unpredictable clinical behavior. Recently, it has been associated with anaplastic lymphoma kinase (ALK) expression. METHODS: Patients under age 16, treated for IMT between 1976 and 2000 were reviewed. Mean follow-up was 8 years (range 1 month-22 years). RESULTS: Eight children had IMT, with a mean age of 6 years (range, 11 months-14 years) and female to male ratio of 3:1. Tumor location was lung (four patients), abdomen (two patients), lung and abdomen (one patient), and abdomen, head, and neck (one patient). Presenting symptoms included anemia (seven patients), fever (six patients), and dyspnea (four patients). Laboratory results included thrombocytosis (six patients), hypergammaglobulinemia (four patients), elevated sedimentation rate (four patients), and leukocytosis (three patients). Immunohistochemistry revealed ALK expression in four of eight tumors. Four children had complete resection and are alive. Two of these children had ALK-positive tumors. Four patients had incomplete resection, and two had recurrences treated successfully with resection and radiotherapy; the other two died of disease. For the incomplete resection patients, those that were ALK-positive lived, and those that were ALK-negative did not. CONCLUSIONS: Eight children were treated for IMT over a 15-year period. ALK expression was found in half the tumors. Prognosis was improved with ALK expression and complete surgical resection.

Adolescent↗

PubMed2006

Paraneoplastic syndrome and intrathoracic Castleman disease.

We report two cases of intrathoracic Castleman disease presenting with paraneoplastic syndrome. Patient 1 was a 10-year-old girl with short stature. She was found to have delayed bone age, slow growth velocity, and iron-deficiency anemia, which was refractory to treatment. Thrombocytosis and hypergammaglobulinemia were later detected. Chest X-ray revealed a hilar mass. Patient 2 was a 14-year-old boy who had severe cough, progressive mucocutaneous erosion, and dermatitis. Chest X-ray showed a mediastinal mass. Sections of skin biopsy showed findings consistent with pemphigus disease. In each case, the histological diagnosis of Castleman disease was made.

Adolescent↗

PubMed1997

Leukemia inhibitory factor induces in vivo expansion of bone marrow progenitor cells that accelerate hematopoietic reconstitution but do not enhance radioprotection in lethally irradiated mice.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine with distinct hematopoietic activities. In vivo treatment of mice with recombinant murine LIF induces thrombocytosis and increases the number of hematopoietic progenitor cells (HPCs) in spleen and bone marrow (BM). In this study, we applied LIF to expand HPCs in vivo prior to syngeneic BM transplantation. BALB/c donor mice were treated with recombinant human LIF at a dose of 2.5 microg/day s.c. for seven days. This resulted in a 1.6-fold increment in platelet counts from 941 to 1,470 x 10(9)/l (mean, n = 20). Mean spleen weight increased from 120 mg to 160 mg (n = 5). The total numbers of HPCs in the spleen as well as in the BM, as assessed in a CFU-GM (colony forming unit-granulocyte-macrophage) assay, were significantly higher in LIF-treated donors than in saline-treated controls (30.1 +/- 14.5 versus 7.4 +/- 5.3 x 10(3) per spleen; mean +/- SD, n = 22,p < 0.001 and 74.4 +/- 17.1 versus 55.3 +/- 16.1 x 10(3) per femur, p < 0.001). Recipient mice were lethally (8.5 Gy) irradiated and transplanted with 3 x 10(5) BM cells derived from LIF- or saline-treated donors. Hematopoietic reconstitution was monitored by tail bleeding at three-day intervals. Platelet and WBC nadir counts in control animals were reached at day 9 (31 +/- 25 x 10(9)/l for platelets and 0.40 +/- 0.10 x 10(9)/l for WBC; mean +/- SD, n = 29 per treatment group); in animals transplanted with LIF-treated BM cells, these counts were 44 +/- 25 x 10(9)/l for platelets, p < 0.05 and 0.60 +/- 0.38 x 10(9)/l for WBC, p < 0.01. In addition, platelet reconstitution was faster in recipients of LIF-treated BM cells (226 +/- 118 versus 126 +/- 62 x 10(9)/l at day 12 and 633 +/- 174 versus 434 +/- 180 x 10(9)/l at day 15, p < 0.001). Similarly, the reconstitution of WBC was also significantly enhanced. The radioprotection rate of lethally irradiated recipients with increasing cell doses of BM cells derived from LIF-treated donors was higher at all cell doses tested then of control animals, but did not reach statistical significance. These results show that in vivo treatment with LIF expands the number of committed progenitor cells and BM repopulating cells that accelerate short-term hematopoietic reconstitution without increasing radioprotection. Our data do not support a major role for LIF as a single factor inducing expansion of hematopoietic stem cells in vivo.

Animals↗

PubMed1997

Differential effect of erythropoietin and GM-CSF on megakaryocytopoiesis from primitive bone marrow cells in serum-free conditions.

In this study we have explored the effect of recombinant human erythropoietin (EPO) and recombinant murine GM-CSF on megakaryocyte progenitors (colony forming units-megakaryocyte [CFU-Mk]) using a serum-free fibrin clot assay and enriched primitive hematopoietic progenitors of marrow cells from day 4 post-5-fluorouracil-treated mice. We have monitored the production of high proliferative potential-colony forming cells ([HPP-CFC]; compact colonies, > 0.5 mm) and studied their relationship to CFU-Mk formation. EPO induced the formation of small numbers of megakaryocyte colonies, but acted together with the megakaryocyte-stimulating factors, stem cell factor (SCF) and interleukin (IL-3), to augment the size of CFU-Mk (colonies with > 50 megakaryocytes/colony). A strong correlation between the number of CFU-Mk and HPP-CFC formation from 5-fluorouracil bone marrow cells was observed when these cells were stimulated with EPO in the presence of SCF and IL-3. On the other hand, GM-CSF alone had no effect on megakaryocyte colony formation. Moreover, GM-CSF in the presence of SCF and IL-3 potentiates the HPP-CFC formation (i.e., an increase of 3.1-fold compared to the effect induced by SCF+IL-3) with strong inhibitory effects on the number and size of megakaryocyte colonies. Although several studies suggest that EPO and GM-CSF can stimulate megakaryocytopoiesis, our results indicate that neither EPO nor GM-CSF alone are sufficient to stimulate primitive progenitors committed to the megakaryocyte lineage. The fact that EPO can exert a strong effect on the size of CFU-Mk induced by SCF/IL-3 suggests that only those megakaryocyte progenitors previously stimulated by other megakaryocyte stimulating factors are able to respond to EPO. These findings may explain the physiological and clinical observations in which high levels of EPO are often associated with thrombocytosis.

Animals↗

PubMed1999

Pharmacokinetics and hematological effects of the PEGylated thrombopoietin peptide mimetic GW395058 in rats and monkeys after intravenous or subcutaneous administration.

GW395058, a potent PEGylated peptide human thrombopoietin receptor (HuTPOr) agonist in vitro, is being evaluated for the treatment of thrombocytopenia. GW395058 shares no sequence homology with TPO. In this report the pharmacokinetics and hematological effects of GW395058 in rats and monkeys are described. Doses eliciting thrombocytosis in rodents (2 or 10 microg/kg s.c.) produced insufficient plasma concentration data for pharmacokinetic parameter estimate calculations. At higher i.v. doses in rats (500, 1,000 or 2,000 microg/kg) serum t1/2 (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t1/2 values ranged from 37 to 68 h after s.c. or i.v. dosing, and similar values were observed in rhesus monkeys following s.c. dosing. Rat platelet counts increased following 2 (1.6-fold) or 10 microg/kg (fourfold) s.c. doses. Cynomolgus and rhesus monkey platelet counts did not change significantly at comparable s.c. doses, but did increase slightly (<twofold) in cynomolgus monkeys following a 25 microg/kg s.c. dose and twofold following a 100 microg/kg s.c. dose. Because the plasma t1/2 of GW395058 is long in mouse, rat, dog, and monkey, yet the dose required to double platelet levels in monkeys is 50-fold that required in rats, differences in hematological responses may be due to interspecies differences in the interaction of GW395058 with the TPOr.

Amino Acid Sequence↗

PubMed1990

Genetic and physiological variations in megakaryocyte DNA content distributions.

The DNA content of normal megakaryocytes usually ranges from 8N to 64N, with 16N as the modal DNA content. The frequency of cells at each DNA content can be altered by experimental induction of thrombocytopenia, thrombocytosis or marrow ablation, and in various disease states; however, the mechanisms and regulation involved in the process of polyploidization remain obscure. This discussion will focus on genetic and physiologic variations in megakaryocyte DNA content distributions. The genetic variations are those we have observed among mouse strains, with the most pronounced present in several C3H substrains in which the modal megakaryocyte DNA content is 32N, rather than 16N. The physiologic variation reported here is a shift to the right in megakaryocyte DNA content distributions during late pregnancy in the rat.

Animals↗

PubMed1990

The control of megakaryocyte ploidy and platelet production: biology and pathology.

Following experimental platelet destruction in animals, large platelets, which are more hemostatically active, are produced before any change in bone marrow megakaryocyte DNA content. When platelet production is stimulated by administration of i.v. vincristine in rats, megakaryocyte ploidy is increased, but mean platelet volume is unchanged. When platelet production and destruction are both stimulated by chronic hypoxia or administration of anti-platelet serum, mean platelet volume and megakaryocyte DNA content are both increased. Since platelet volume is determined primarily at thrombopoiesis, these results imply that mean platelet volume and megakaryocyte DNA content are under separate hormonal control. Therefore, it has been postulated that changes in mean platelet volume occur following changes in platelet production rate, whereas changes in megakaryocyte ploidy are associated with an increased rate of platelet production. In myocardial infarction, platelets have increased mean volume and reduced bleeding time more than in controls. In addition, men with myocardial infarction have increased megakaryocyte size and increased DNA content when compared to controls. These changes are similar to those observed in rabbits following cholesterol feeding. If megakaryocyte polyploidy and mean platelet volume are under separate hormonal control, this suggests that in myocardial infarction, both hormones are active--one stimulating an increased platelet size, the other stimulating the increased megakaryocyte DNA content. In contrast, patients with lymphoma exhibiting a secondary thrombocytosis have no change in mean platelet volume. However, these subjects also have larger bone marrow megakaryocytes when compared to controls. The relation between megakaryocyte size and ploidy implies that the DNA content of these cells is increased in lymphoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Physiologic role of TPO in thrombopoiesis.

Recombinant human thrombopoietin (rHuTPO) serves as a megakaryocyte colony-stimulating factor and predominantly acts on GPIIb/IIIa+ rat late megakaryocyte progenitor cells, colony forming units-megakaryocyte (CFU-MK). The GPIIb/IIIa+ fraction of CFU-MK differentiates into mature megakaryocytes and further into proplatelets in liquid culture containing rHuTPO. rHuTPO stimulates cultured megakaryocytes generated from rat GPIIb/IIIa+ CFU-MK to enhance proplatelet formation and to increase megakaryocyte size. rHuTPO also induces a big size of megakaryocyte colonies from human cord blood CD34+ cells. rHuTPO does not cause aggregation of platelets from normal mice and mice made thrombocytotic by consecutive administration of rHuTPO, but preincubation with rHuTPO enhances adenosine diphosphate-induced aggregation, suggesting that platelets induced by rHuTPO administration may have a normal function. Administration of rHuTPO to normal mice daily for five days causes a dose-dependent thrombocytosis. On the other hand, rHuTPO induces a significant decrease in hemoglobin concentration and does not affect white blood cell counts. rHuTPO increases the size and number of marrow megakaryocytes and the number of marrow CFU-MK, and also influences the development of other hematopoietic progenitor cells. The effects of rHuTPO on thrombocytopenia associated with myelosuppression were examined in animal models. Following treatment with mitomycin C, mice received daily injections of various doses of rHuTPO. rHuTPO reduced the severity of thrombocytopenia, accelerated the recovery of platelets and improved neutropenia. Similar therapeutic efficacy was observed in cynomolgus monkeys treated with nimustine. These results suggest the clinical usefulness of rHuTPO for the treatment of thrombocytopenia.

Adenosine Diphosphate↗

PubMed1998

A novel thrombopoietin signaling defect in polycythemia vera platelets.

The pathogenesis of polycythemia vera (PV), a disease involving a multipotent hematopoietic progenitor cell, is unknown. Thrombopoietin (TPO) is a newly characterized hematopoietic growth factor which regulates the production of multipotent hematopoietic progenitor cells as well as platelets. To evaluate the possibility that an abnormality in TPO-mediated signal transduction might be involved in the pathogenesis of PV, we examined TPO-induced protein tyrosine phosphorylation using platelets as a surrogate model system. Platelets were isolated from the blood of patients with PV as well as from patients with other chronic myeloproliferative disorders and control subjects. Impaired TPO-mediated platelet protein tyrosine phosphorylation was a consistent observation in patients with PV as well as those with idiopathic myelofibrosis (IMF), in contrast to patients with essential thrombocytosis, chronic myelogenous leukemia, secondary erythrocytosis, iron deficiency anemia, hemochromatosis, or normal volunteers. Thrombin-mediated platelet protein tyrosine phosphorylation was intact in PV platelets as was expression of the appropriate tyrosine kinases and their cognate substrates. However, expression of the platelet TPO receptor, Mpl, as determined by immunoblotting, chemical crosslinking or flow cytometry was markedly reduced or absent in 34 of 34 PV patients and also in 13 of 14 IMF patients. Impaired TPO-induced protein tyrosine phosphorylation in PV and IMF platelets was uniformly associated with markedly reduced or absent expression of Mpl. We conclude that reduced expression of Mpl is a phenotypic characteristic of platelets from patients with PV and IMF. The abnormality appears to distinguish PV from other forms of erythrocytosis and may be involved in the platelet function defect associated with PV.

Blood Platelets↗

PubMed1998

Leukocyte function in chronic myeloproliferative disorders.

The myeloproliferative disorders (MPD) are clonal diseases that originate from a transformed stem cell and involve all myeloid lineage. The affected cells have both proliferative and functional impairment. Therefore, we evaluated and compared neutrophil function in 31 patients with polycythemia vera (PV), idiopathic myelofibrosis (MF), chronic myeloid leukemia (CML), and essential thrombocytosis (ET). Neutrophil chemotaxis, random migration, bactericidal activity and superoxide anion release in these patients were simultaneously compared to those of 31 healthy controls. In this study, chemotactic activity was significantly impaired in patients with PV and CML as compared to controls (M+/-SE: 42 +/- 6 vs. 69+/- 5 cells/field; p<0.005 and 47+/-7 vs. 68+/- 5; p<0.05, respectively). The assessment of the bactericidal activity of neutrophils showed no impairment in most of the patients. In the CML group, the serum had a very strong "lytic" effect on bacteria, possibly due to the high levels of serum lysozyme (22 +/- 2 microgram/ml). The superoxide anion release was found to be normal in most of the patients. Nevertheless, in 25% of PV patients the superoxide production was impaired (less than 60% of the simultaneous controls). In ET most patients had normal neutrophil function. Regarding the effect of treatment, neutrophil chemotactic activity was found to be significantly reduced in the hydrea-treated patients, as compared to the non- treated patients (p<0.001) or healthy controls (<0.0001). We conclude that disturbances in neutrophil function are present in patients with various MPDs, except ET. This probably reflects abnormal maturation of ancessors of the damaged stem cells. Nevertheless, we should keep in mind that therapy itself could affect neutrophil functions. This matter should be studied more extensively. Although infections are not common in MPD disorders, they occasionally occur. It is possible that impairment in the phagocytic function contribute to the development of infections in patients with myeloproliferative disorders.

Adult↗

PubMedDate not supplied

Model mice for BCR/ABL-positive leukemias.

p210bcr/abl is detected in almost all chronic myelogenous leukemia (CML) patients and a significant number of acute lymphoblastic leukemia (ALL) cases. It is generated by a reciprocal chromosomal translocation, t(9;22) (q34;q11), and the enhanced kinase activity of the protein is believed to be implicated in the pathogenesis of the diseases. To examine its oncogenicity in vivo and to create an animal model for BCR/ABL-positive leukemias, we generated transgenic mice expressing p210bcr/abl driven by the promoter of the mouse tec gene, a cytoplasmic tyrosine kinase preferentially expressed in early hematopoietic progenitors. While the founder mice showed excessive proliferation of lymphoblasts shortly after birth and were diagnosed as ALL, the transgenic progeny reproducibly exhibited marked granulocyte hyperplasia with thrombocytosis after a long latent period, which closely resembles the clinical course of human CML. In addition, to investigate whether loss of p53 would play a role in the transition from chronic phase to blast crisis of CML, we crossmated p210bcr/abl transgenic (BCR/ABLtg/-) mice with p53 heterozygous (p53+/-) mice and generated p210bcr/abl transgenic, p53 heterozygous (BCR/ABLtg/- p53+/-) mice, in which a somatic alteration in the residual p53 allele directly abrogates p53 function. The BCR/ABLtg/- p53+/- mice exhibited rapid proliferation of blast cells and died in a short period compared with their wild-type (BCR/ABL-/- p53+/+), p53 heterozygous (BCR/ABL-/- p53+/-), and p210bcr/abl transgenic (BCR/ABLtg/- p53+/+) littermates. Interestingly, the normal p53 allele was frequently and preferentially lost in the tumor tissues, providing in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210bcr/abl-expressing hematopoietic cells. Our transgenic mice will be a useful model for investigating oncogenic properties of p210bcr/abl in vivo and will provide insights into the molecular mechanism(s) underlying the progression from chronic phase to blast crisis of CML.

Animals↗