Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Jumping translocations (JT) are characterized by the relocalization of the same part of a donor to several recipient chromosomes. Although JT occasionally are constitutional, most are associated with hematologic malignancies. In such cases, JT usually arise during disease progression and are associated with poor prognosis. Despite its clinical importance, this cytogenetic phenomenon has not been characterized at the molecular level. We have analyzed JT in a juvenile chronic myelomonocytic leukemia that subsequently transformed to an acute myeloid leukemia. Detailed fluorescence in situ hybridization (FISH) analyses showed that the cytogenetically identical donor breakpoint at 3q21 was highly heterogeneous. In fact, more than 10 distinct breakpoints, four of which mapped within YACs, were identified. Analyses of samples during disease progression showed that the breakpoint complexity decreased, indicating clonal selection. Hence, the 3q21 breakpoints displayed a spatial as well as a temporal heterogeneity, revealing that JT are highly unstable, showing great variation in the size of donor segment. The breaks at the recipient chromosomes were mapped within the subtelomeric regions. The general telomere length was not affected and an underlying replication error resulting in microsatellite instability was excluded. We conclude that the emergence of JT is unlikely to cause fusion genes or to affect the expression of genes located in the breakpoint regions. The identification of YACs spanning the breakpoints, ie, YACs 913c7, 937g5, 948c2 and 955g1, may facilitate the isolation of DNA sequences leading to a genetic instability associated with the origin of multiple translocations.
Leukemia 1998 Sep
PMID:Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity. 973 90

A new human leukemia cell line with an eosinophilic phenotype, designated YJ, was established from the peripheral blood cells of a patient with chronic myelomonocytic leukemia (CMMoL) with eosinophilia. When cultured in RPMI 1640 medium containing 10% fetal bovine serum, most YJ cells were myeloblastoid with a small number of the cells having eosinophilic granules. Cell surface markers in the YJ cells were positive for CD33 and were negative for CD34, CD16 and CD23. The eosinophilic characteristics of YJ cells were confirmed by histochemical staining with Fast-Green/Neutral-Red and by the expression of mRNAs for eosinophil-associated granule proteins, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), eosinophil peroxidase (EPO), and major basic protein (MBP), and for the Charcot-Leyden crystal (CLC) protein. The YJ cells could be induced towards monocytic differentiation by stimulation with phorbol 12-myristate 13-acetate (PMA). The monocytic characteristics of YJ cells treated with PMA were confirmed by morphological analysis with alpha-naphthyl butyrate esterase staining, by CD14 expression, and by increased expression of Egr-1 mRNA. Furthermore, YJ cells could be differentiated towards the neutrophil lineage by stimulation with all-trans retinoic acid (RA). YJ cells treated in vitro with 2 microM RA differentiated into metamyelocytes and band neutrophils, and increased the number of nitroblue tetrazolium (NBT)-positive cells and increased gp91phox mRNA expression. Thus, the YJ cell line exhibited eosinophilic characteristics, but was able to differentiate to the monocytic or neutrophilic lineages in response to PMA or RA, respectively. The expression of genes for transcription factors involved in myeloid differentiation was evaluated by Northern blot analysis. Increased expression of Egr-1 was observed with macrophage differentiation. In contrast, increased expressions of C/EBPbeta and MZF-1 mRNA occurred with neutrophilic differentiation. The YJ cell line should be useful for elucidating the molecular mechanisms governing lineage switching from the eosinophil to monocytic or neutrophil lineages.
Leukemia 1998 Sep
PMID:Models of lineage switching in hematopoietic development: a new myeloid-committed eosinophil cell line (YJ) demonstrates trilineage potential. 973 93

Topotecan and retinoids are among the most promising agents being evaluated for the treatment of acute myelogenous leukemia (AML), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-t). Single-agent topotecan is similar to single-agent ara-C, but may be superior in patients with poor-prognosis chromosome abnormalities (ie, -5,-7). Topotecan plus ara-C is equivalent to topotecan alone in chronic myelomonocytic leukemia (CMML), but significantly more effective in RAEB and RAEB-t. Compared with single-agent ara-C, the complete remission (CR) rate with topotecan plus ara-C is comparable, although it offers special advantages in patients with the -5,-7 karyotype. In patients with poor-prognosis cytogenetics, the combination of cyclophosphamide, ara-C, and topotecan, plus all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF) appears favorable. In a recent study of triple-agent chemotherapy using fludarabine, ara-C, and idarubicin, with or without ATRA and G-CSF, median survival among poor-prognosis patients was 6-7 months, but those who received ATRA did better than those who did not, primarily because it improved survival in those who did not achieve CR. G-CSF produced higher CR rates but had no effect on survival or disease-free survival.
Leukemia 1998 Sep
PMID:New agents for the treatment of acute myelogenous leukemia: focus on topotecan and retinoids. 977 88

Myelodysplastic syndromes (MDS) caused by a clonal hematopoietic stem cell disorder progress to either overt leukemia or cytopenia, which leads to lethal infection or bleeding. Although several clinical trials have attempted to reverse cytopenia by using hematopoietic growth factors (HGF), success has been limited due in part to a limited understanding of the role of HGF in MDS progression. The FLT3 ligand, which binds to and activates the FLT3 receptor, does not have a stimulatory effect on hematopoietic cells, but can synergize with other HGF to support the expansion of both immature and committed progenitors. Using ELISA technology we measured endogenous serum levels in 93 patients with MDS: 29 RA, 1 RARS, 31 RAEB, 23 RAEBt, 9 CMML. 48.3% of RA patients' sera had significantly elevated FLT3 ligand levels ranging from 404 to 5735 pg/ml, whereas none of the RAEB, RAEBt, or CMML patients sera had levels different from controls. No significant correlation was found between FLT3 ligand levels and peripheral blood counts, bone marrow cellularity, age, cytogenetic abnormalities, or survival. Our data suggest that FLT3 ligand levels can be upregulated early in the course of MDS, which may represent an appropriate response to a decreased number of normal progenitors, or alternatively a dysregulated HGF system.
Leukemia 1999 Apr
PMID:Endogenous FLT-3 ligand serum levels are associated with disease stage in patients with myelodysplastic syndromes. 1021 61

Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are thought to arise from malignant hematopoietic progenitor cells representing early and undifferentiated stem cell clones. In CML there is evidence for a progenitor cell subset free of leukemic clones, depending on the course of the disease. Additionally, it has been suggested that in AML, the early stem cell compartment (CD34+/90+) does not harbor the malignant clone. We analyzed white blood cells from leukemia patients for the presence of aberrant cells in stem cell subfractions. Sixteen patients with CML, six patients with AML, two patients with acute lymphatic leukemia (ALL) and one with chronic myelomonocytic leukemia (CMMOL), all with known cytogenetic abnormalities, were evaluated according to their CD90 (Thy-1)-positive or -negative phenotype. Subsets were sorted on to slides and further characterized by FISH and/or standard cytogenetic testing. The bcr-abl translocation or gross chromosomal abnormalities could be detected in equally high amounts of 92.2% and 89.2% in both stem cell subsets. We conclude, that in progressed AML and CML cells characterized by specific genetic aberrations implicated in the malignant state can be found in the CD34+/CD90+ and CD90- population, thus making CD90 an inappropriate marker to distinguish benign from malignant cells in these leukemias.
Leukemia 1999 Nov
PMID:Detection of cytogenetic aberrations both in CD90 (Thy-1)-positive and (Thy-1)-negative stem cell (CD34) subfractions of patients with acute and chronic myeloid leukemias. 1055 51

Chronic myelomonocytic leukemia (CMML) is a pre-leukemic syndrome that displays both myelodysplastic and myeloproliferative features. The t(5;12) chromosomal translocation, present in a subset of CMML patients with myeloproliferation fuses the amino terminal portion of the ets family member, Tel, with the transmembrane and tyrosine kinase domains of platelet-derived growth factor receptor beta (PDGFRbeta) gene. To investigate the role of this fusion protein in the pathogenesis of CMML, we expressed the Tel-PDGFRbeta fusion cDNA in hematopoietic cells of transgenic mice under the control of the human CD11a promoter. Transgenic founders and their offspring express the transgene specifically in hematopoietic tissues and develop a myeloproliferative syndrome characterized by: overproduction of mature neutrophils and megakaryocytes in the bone marrow; splenomegaly with effacement of splenic architecture by extramedullary hematopoiesis; an abnormal population of leukocytes co-expressing lymphoid and myeloid markers; and increased numbers of colonies in in vitro bone marrow CFU assays. All mice expressing the transgene exhibited at least one of these features of dysregulated myelopoiesis, and 20% progressed to a myeloid or lymphoid malignancy. This murine model of CMML parallels a myeloproliferative syndrome in humans and implicates the Tel-PDGFRbeta fusion protein in its pathogenesis.
Leukemia 1999 Nov
PMID:The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice. 1055 54

The biological and clinical importance of cytogenetic analysis in myelodysplastic syndrome (MDS) and in acute myeloid leukemia (AML) is being increasingly recognized. Recently, cytogenetic similarities were noted between elderly de novo AML and secondary AML, suggesting common etiopathogenetic mechanisms. In the present study we analyzed the cytogenetic similarities between patients with AML of different age and patients with MDS consecutively diagnosed during a 5-year period at a single, primary referral, hematologic center. Of 246 patients aged <86 years, 195 (80%) had a cytogenetic study at diagnosis. Informative metaphases were obtained in 182 cases (93%), including 17 (9.3%) with secondary MDS/AML. Patients were classified according to FAB criteria and were subdivided into four groups: (1) 'early MDS': 42 patients with MDS of FAB subtypes other than refractory anemia with excess of blasts (RAEB) or RAEB in transformation (RAEB-T); (2) 'late MDS': 35 patients with RAEB and RAEB-T; (3) 'old AML': 48 patients with AML aged 65 to 85 years; (4) 'young AML': 57 patients with AML aged <65 years. Results showed that 'late MDS' and 'old AML' had striking cytogenetic similarities both in the frequency of normal karyotypes (31% and 27%), single abnormalities (14% and 13%), double abnormalities (17% and 14%), complex karyotypes (37% and 46%), and numerical abnormalities (89% and 93%), as well as in the frequency of rearrangements involving chromosome 5 (20% and 31%) and 7 (27% and 27%). The only difference between the two groups was found in the median number of chromosomes involved in complex karyotypes (5 vs 8; P=0.03). 'Early MDS' had significantly less complex karyotypes (21%; P<0.05), but its cytogenetic features resembled otherwise those of 'late MDS' and 'old AML', and any significant difference disappeared when patients with chronic myelomonocytic leukemia (CMML) were excluded. CMML markedly differed from other MDS subtypes in the frequency of normal (57%) and of complex karyotypes (6%). Secondary MDS/AML and AML with trilineage dysplasia shared the same cytogenetic features of 'late MDS' and 'old AML'. 'Young AML' strikingly differed from all other groups, particularly in the higher frequency of balanced translocations (29%; P<0.001) and single karyotype abnormalities (32%; P<0.02), and in the lower frequency of complex karyotypes (19%; P<0.01) and of chromosome 5 (2%; P<0.001) and 7 (9%; P<0.01) involvement. We conclude that in a population-based series of patients, the cytogenetic profile of MDS, particularly of RAEB/RAEB-T, was nearly identical to that of elderly patients with AML both in the frequency and in the type of chromosomal abnormalities. These results support the possibility that MDS and AML of elderly patients may represent the same disease seen at different stages of evolution.
Leukemia 2000 Apr
PMID:Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients. 1076 49

Interleukin-12 (IL-12) has potent antitumor activities. We examined whether IL-12 enhanced the cytotoxicity of peripheral blood mononuclear cells (PBMNC) and decreased leukemia cells in 30 patients with leukemia or myelodysplastic syndromes (MDS): 12 acute myeloid leukemia (AML) (five in complete remission (CR) and seven in non-CR); six chronic myeloid leukemia (CML); and 12 MDS (three refractory anemia (RA), eight RA with excess of blasts and one chronic myelomonocytic leukemia). PBMNC from patients and five healthy volunteers were cultured at 5 x 10(5)/ml parallel with or without 100 units/ml of IL-12 for 3 days. Cytotoxicity of PBMNC against K562 cells was assessed by flow cytometry. To quantify the amount of leukemia cells, WT1 mRNA was measured by competitive reverse transcription polymerase chain reaction (RT-PCR), since WT1 mRNA is considered as a marker of minimal residual disease (MRD) in leukemia or MDS. The cytotoxicity of non-IL-12-treated PBMNC of 30 patients was 13.4+/-9.3% at the effector to target (E:T) ratio of 20:1, and significantly lower than that of normal subjects (25.7+/-8.4%). The cytotoxicity increased to 30.6+/-17.9% in the IL-12-treated PBMNC. WT1 mRNA in PBMNC of five healthy volunteers was less than 10(3) copies/microg of total RNA. Following the 3-day IL-12 treatment, mean WT1 mRNA of PBMNC was reduced from 10(4.8) to 10(4.2) copies/microg of total RNA in six CML patients, from 10(5.4) to 10(4.8) copies/microg in 12 MDS patients and from 10(5.0) to 10(4.2) copies/microg in five AML patients in CR, but not reduced in five of seven AML in non-CR. These results showed that IL-12 significantly enhanced PBMNC cytotoxicity and decreased the quantity of leukemia cells in PBMNC of most patients with MDS, CML and AML in CR. IL-12 might be of considerable benefit in the elimination of MRD in patients with hematological malignancies.
Leukemia 2000 Sep
PMID:In vitro IL-12 treatment of peripheral blood mononuclear cells from patients with leukemia or myelodysplastic syndromes: increase in cytotoxicity and reduction in WT1 gene expression. 1099 11

Aberrant expression of FLT3 has been found in most cases of B-lineage ALL and AML, and subsets of T cell ALL, CML in blast crisis and CLL. In 20% of patients with AML the receptor has small internal tandem duplications of the juxtamembrane region which appear to contitutively activate the receptor. To investigate whether FLT3 activation could play a role in leukemia, we generated a constitutively activated FLT3 by fusing its cytoplasmic domain to the helix-loop-helix domain of TEL in analogy to the fusion that occurs with TEL-PDGFR in CMML. In vitro translation assays demonstrated oligomerization and intrinsic tyrosine kinase activity of the TEL-FLT3 chimeric receptor. Constitutively activated TEL-FLT3 conferred IL-3 independence and long-term proliferation to transfected Ba/F3 cells. Immunoblot analyses showed that JAK 2, STAT 3, STAT 5a, STAT 5b and CBL were tyrosine-phosphorylated in TEL-FLT3 expressing Ba/F3 cells in the absence of IL-3. These data suggest a possible role for the JAK/STAT pathway in FLT3 signaling. Transplantation of TEL-FLT3 expressing Ba/F3 cells into syngeneic mice caused mortality in all mice by 3 weeks after injection. Histopathologic analysis demonstrated a massive infiltration of mononuclear cells in the liver, spleen and bone marrow. The mimicking of naturally occurring TEL fusions provides an approach to assess aspects of the biology of activated FLT3, or other receptor-type tyrosine kinases (RTKs) in leukemic transformation.
Leukemia 2000 Oct
PMID:Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. 1102 52

Myelodysplastic syndromes (MDS) are characterized by abnormal growth of committed progenitors in clonogenic assay, with reduced number of colonies and decreased colony/cluster ratio. It has been suggested that excessive apoptosis is the cause of marrow failure in MDS. We studied the expression of caspase-1 (interleukin-1beta-converting enzyme, ICE) and caspase-3 (CPP32/apopain) in marrow mononuclear cells, and the growth pattern of committed progenitors in a series of 83 MDS cases. The percentage of apoptotic cells as detected by TUNEL technique, and the percentage of caspase-3-positive cells were significantly higher in refractory anemia (RA) and RA with ringed sideroblasts (RAS) than in chronic myelomonocytic leukemia (CMML), refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-T). Spontaneous growth of CFU-GM was associated with a higher percentage of blasts, and with a lower expression of caspase-3 and caspase-1. The yield of CFU-E, BFU-E, and CFU-GM (in the presence of growth factors) was decreased by comparison to normal marrow, but large individual differences were observed in all cytological categories. Inhibition of caspase-1 and caspase-3 activities by specific inhibitors resulted in a significant increase of the production of all types of colonies (up to 50-fold of control). In the presence of caspase-3 inhibitor, the number of BFU-E and CFU-E was in the range of normal values in most cases of RA and RAS. In addition, caspase-1 and -3 protease activities were detectable by fluorogenic assay in all cases studied. Western blot analysis confirmed the expression of caspase-3, including the cleaved (activated)-p17 form in most cases of RA/RAS analyzed. It is concluded that caspase-3 is implicated in the increased apoptosis observed in MDS and that inhibition of its activity can restore at least partially the growth of committed progenitors.
Leukemia 2000 Dec
PMID:Expression and activity of caspases 1 and 3 in myelodysplastic syndromes. 1118 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>