Hematology and cell therapy最新文献

It is currently well established that chronic myelogeneous leukemia (CML) results from the activation of multiple signalling pathways by the Philadelphia chromosome (Ph1) and its molecular counterpart, the BCR-ABL oncogene. Deletion and site-directed mutagenesis experiments have determined the critical regions of the oncogene for its interaction with major signalling pathways but the roles of the latter in the resulting leukemic phenotypes are not well understood. Several major signalling pathways shown to be activated by BCR-ABL, including RAS, MYC, JUN, STAT, PI-3K and NF-KB are briefly discussed in this paper. Other signalling molecules are also clearly involved, including p62-DOK, p95-VAV, CRK-L, p12O-CBL and focal adhesion proteins. Recent experimental evidence also indicates that negative regulatory proteins could be activated in cells expressing BCR-ABL and their inhibition during the course of the disease could play a role in the progression towards the acute phase. We finally discuss the evidence indicating that at least in experimental systems BCR-ABL has a clear anti-apoptotic activity and that BCR-ABL achieves this effect by acting upstream of the procaspase-3.

Interferon-alpha has been shown to induce complete haematologic responses in chronic myelogenous leukemia patients and also cytogenetic responses. There is a clear correlation between cytogenetic responses and survival improvement. There is not a unique mechanism of action of IFN-alpha. IFN-alpha acts directly against leukemic cells and there are also other mechanisms of action such as immune stimulation, gene regulation and growth factors or interleukin stimulation.

The availability of animal models of the APS has provided a lot of experimental data which might be considered in trying to unravel several questions concerning this complicated disease. The main clinical manifestations associated with this disorder are repeated pregnancy loss, thrombocytopenia and thrombotic events. Other manifestations have been reported in relation to APS. However, the association with anti-phospholipid antibodies (aPL) are still uncertain. In the APS murine models presented here, both the Lupus-prone mice and the naive mice with induced APS, fetal resorption (parallels to embryo loss) and reduced fecundity rate were prominent features strongly associated with pathogenic aCL antibodies, making these models appropriate for investigating the human disease. Utilizing these models for APS have enabled to show the pathogenicity of aPL in pregnancy loss, neurological and behavioral changes, renal involvement and thrombus formation. Antiphospholipid antibodies from patients with APS, as well as natural aCL antibodies exerted pathogenic effects in naive mice, and in an in vivo thrombosis model. Several therapeutic modalities were found promising for application in the clinics. These include the antithrombotic and anticoagulant treatments using aspirin or LMWH, IL-3, or immunomodulation by high dose IVIG, specific anti-idiotypic or anti-CD4 antibodies, cyprofloxacin or bromocriptin administration.

Clinical, morphological, cytogenetic and molecular (fluorescence in situ hybridization and RT-PCR) data were analyzed in twelve Philadelphia negative chronic myeloid leukemias (Ph-negative CMLs). Four patients were classified as BCR-positive. A standard b2a2 or b3a2 transcript was found, and the BCR-ABL hybrid gene was located on the 22q11 band in three cases and on the 1p35 band in one case with a t(1;9)(p35;q34). All were classified as typical chronic granulocytic leukemia (CGL) according to the French-American-British (FAB) morphological guidelines. Responses to therapy were evaluated by FISH in the four patients, and proved to be poorer than in Ph-positive CMLs. Eight BCR-negative patients were identified. They could be characterized by an older age, a less proliferative form of disease than the BCR-positive patients, and a frequent (six out of eight) abnormal karyotype. The FAB classification identified four CGLs and four atypical CMLs (aCML). A normal karyotype was more frequent in the patients classified as CGL whereas all the aCMLs had a chromosomal abnormality. Three patients had chromatin clumping and this morphologic feature was associated with trisomy 8 in two. No correlation between the cytogenetic, morphologic and the clinical data were found. Five patients had poor tolerance to therapy with a frequent occurrence of bone marrow failure and hemorragic syndrome, whereas three patients responded to a standard treatment of CML. Our study reinforces previous data on Ph-negative BCR-positive CMLs and emphasizes the difficulty in correlating clinical, morphologic, cytogenetic data in Ph-negative BCR-negative CMLs. However, our data also argue in favor of the existence of true Ph-negative BCR-negative CMLs and suggest that some of them can respond to a standard treatment of CML.

Hairy cell leukemia represent 2% of all the leukemias. The etiology is unknown. The diagnosis is based on the peripheral blood examination, showing characteristic lymphoid B cells, with loose lacy chromatin and unconstant cytoplasmic projections. The abnormal lymphoid cells express CD19, CD20, CD22, CD79a, CD25 and CD103. The tumor cells are Sig + with clonal light chain restriction. The treatment is based on recombinant IFN: we discuss the interest and the risks of second malignancy related to the prescription of the purine analogues.

An epidemiological study of 842 polycythaemic patients (entered between 1980 and 1997 in the French investigational prospective protocols) is presented. The global incidence is approximately 0.8-1.5/100,000/year in the reference area (Ile-de-France and surrounding areas). It increases linearly with age until 80, which suggests that several mutational somatic events are necessary. There was a slight male excess (sex-ratio 1.2, after correction for the percentage of male and female French people still living at risk). We did observe a slight excess of PV in the population of Jewish ancestry. A surprising excess of former blood donors (20.7% of the PV cases, compared to 8% estimated in the reference population) was observed. Only a few cases of familial myeloproliferative diseases and occurence of leukemia in the family of our patients have been observed; even if slight, this excess is statistically significant. In contrast, no excess of carcinomas was observed either in the family or in the patients' antecedents. We did not find any excess of radiation exposure in our cases. When analysing the previous occupation of our patients a possible excess of physicians and of patients previously working in occupations using solvents and glues was found, but this finding needs confirmation.

Endogenous erythroid colonies (EECs), a typical characteristic of polycythemia vera (PV), could be observed in essential thrombocythemia (ET). Erythroid progenitors culture carried out in 34 previously untreated patients with unequivocal ET showed EECs in 35% of the cases. During a mean follow up of 4 years after the culture, the 12 EECs(+) and the 22 EECs(-) patients did not show any difference for a thrombotic or haemorrhagic complication, and the only one patient who showed an involvement of erythropoiesis was in the EECs(-) group.

A 24-year-old female, in neutropenic phase after chemotherapy for acute myelogenous leukemia (on day 15) was admitted in intensive care unit for infectious pneumonia. Two strains of Stomatococcus mucilaginosus were isolated from peripheral blood cultures. No microorganisms were yielded from bronchoalveolar lavage. Patient's condition improved with prompt instigation of effective antibiotic therapy. This was the first case of septicemia and pneumonia, due to Stomatococcus mucilaginosus, in our unit. Only 26 cases occurring in neutropenic patients with underlying hematologic malignancies were reported in the literature and among these, only five cases with pneumonia were described. The complications of this normal inhabitant of the human oral cavity can be serious and fatal: septic shock, meningitis, acute respiratory distress syndrome. This study illustrate the possible virulence of Stomatococcus mucilaginosus in neutropenic patients.

Antiphospholipid antibodies were investigated in 37 individuals with sickle cell disease and compared to a control group of 30 healthy subjects. Sickle cell patients included 18 homozygous sickle cell patients, 8 S/beta thalassemic patients and 11 sickle cell trait subjects. In all individuals, antiphospholipid antibodies were explored by lupus anticoagulant (LA) detection and the quantification of IgG and IgM anticardiolipin (aCL) isotypes, total antiphospholipid antibodies (APA) and IgM, IgG and IgA antiphospholipid classes. In homozygous sickle cell patients, mean level of IgG aCL and total APA were significantly increased (17.02 +/- 8.88 GPL/ml, p < 0.05 and 10.64 +/- 10.58 UPL/ml, p < 0.05 respectively). The IgG aCL, total APA and LA frequencies were 22.2%, 44.4% and 62.2%, respectively. APA isotypes were mostly IgG or IgG and IgA. In S/beta thalassemic patients, mean levels of APA were significantly increased (10.81 +/- 7.82 UPL/ml, p< 0.05). Their frequency was 71.4% and they were mostly IgG or IgG and IgA. In patients with sickle cell trait, mean levels of APA were significantly increased (10.84 +/- 5.84 UPL/ml, p < 0.01). Their frequency was 72.7% and mostly of IgG isotype. Our study showed a close association between high APA levels and sickle cell syndrome, however there was no relationship between high levels of antiphospholipid antibodies and the major complications of sickle cell disease.