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)

The survival, proliferation, differentiation and function of normal hematopoietic cells are negatively and positively controlled by various cytokines. Survival and proliferation of leukemic cells appears to be influenced, at least in vitro, by several cytokines. Among the different hematopoietic cell lineages, megakaryocytopoiesis represents a complex and unique hematopoietic system that is thought to be supported by some well-known cytokines; however, the hypothetical lineage-specific main regulator of platelet production, termed thrombopoietin (TPO) had remained elusive. Recently, characterization of the proto-oncogene c-mpl revealed structural homology with the hematopoietic cytokine receptor superfamily, specific expression on cells of the megakaryocytic lineage and functional involvement in megakaryocytopoiesis. Several groups purified and cloned the MPL ligand. Extensive in vitro and in vivo studies have shown that the MPL ligand has activity in stimulating both megakaryocytopoiesis and platelet production proving that this ligand is the long-sought growth factor TPO itself. The MPL receptor was found at the mRNA and/or protein level in 40-80% of primary acute myeloid leukemia (AML) cases in various series. MPL expression was not limited to certain morphological FAB types, although the highest percentages were seen in the M6 (erythroid) and M7 (megakaryocytic) subclasses. Among the myelodysplastic syndromes (MDS), MPL expression was detected in one third of the cases, in particular in refractory anemia with excess of blasts and chronic myelomonocytic leukemia. Lymphoid malignancies such as acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL) and myeloma were MPL-negative. Among the large panel of human leukemia-lymphoma cell lines studied, MPL expression occurred predominantly in lines with erythro-megakaryocytic phenotypes. Nearly all primary and continuously cultured non-hematopoietic solid tumor samples were negative for MPL expression. A significant portion of AML cases and of erythroid, megakaryocytic and myeloid leukemia cell lines co-expressed TPO and MPL mRNA transcripts, although no biologically active TPO appeared to be secreted by these cells. In several studies TPO induced in vitro proliferation of 14-37% of primary AML cases, predominantly of the M2 and M7 subtypes. TPO significantly enhanced the cytokine-induced growth of AML cells in a substantial fraction of cases responsive to GM-CSF, IL-3, IL-6 or SCF. While none of 30 growth factor-independent erythro-megakaryocytic leukemia cell lines responded to TPO with increased proliferation, TPO strongly augmented the growth of several constitutively cytokine-dependent cell lines (eg HU-3, M-07e, TF-1) which can be made TPO-dependent and used as bioassays. Neither in primary cells nor in cell lines did TPO appear to induce any signs of morphological, functional or immunological differentiation. Expression of the MPL receptor is not correlated with a proliferative response to TPO. In summary, extensive studies on normal human and animal cells demonstrated the specificity and function of the MPL receptor and proved that its ligand TPO is the major physiological regulator of megakaryocytopoiesis. The data reviewed here document the wide expression of the MPL receptor on AML cells and also suggest some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic AML cells as well. Thus, experimental evidence supports the notion that TPO may contribute, at least in part, to leukemogenesis, especially in combination with other hematopoietic cytokines which is of clinical significance. TPO-responsive cell lines represent powerful tools for such analyses.
Leukemia 1996 Sep
PMID:Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells. 875 57

To evaluate diagnostic criteria, disease characteristics, and the clinical course of pediatric myelodysplastic syndrome (MDS), we reviewed 327 consecutive cases diagnosed with de novo acute myeloid leukemia (AML) or MDS at St Jude Children's Research Hospital between February 1980 and January 1993. Among 49 cases with <30% marrow blasts (consistent with FAB criteria and common diagnostic practice for MDS), eight had karyotypes associated with de novo AML (four with t(8;21)(q22;q22) and one each with inv(16)(p13q22), t(11;17)(q23;q21), t(9;11)(p22;q13), and i(1)(ql0)). We termed these cases AML with a low blast count (AML-LBC) and compared their clinical and morphologic features with those of the remaining 41 cases. AML-LBC cases had little or no hematopoietic dysplasia. MDS cases consisted of refractory anemia (RA, n=6), RA with ring sideroblasts (n=2), RA with excess blasts (RAEB, n=4), RAEB in transformation (n=14), and chronic myelomonocytic leukemia (n=15). Most had moderate/severe or multilineage hematopoietic dysplasia, with significantly higher dysplasia scores than AML-LBC cases (P=0.007). Only 30% of patients with MDS achieved complete remission (CR) after two cycles of AML-directed therapy, compared with 88% of patients with AML-LBC (P=0.0001); MDS patients tended to experience prolonged severe cytopenias with chemotherapy. The 4-year survival for MDS patients was 23% +/- 7% (s.e.), vs 50% +/- 18% (s.e.) for AML-LBC (P=0.048). AML-LBC patients frequently had chloromas; none were seen in MDS patients. We conclude that the 30% blast threshold is ineffective for separation of AML and MDS in pediatric patients, and that genetic data should be included in this decision process. AML-LBC, defined by <30% blasts in bone marrow and cyto- (or molecular) genetic abnormalities associated with de novo AML, and characterized by absent or mild marrow dysplasia, is biologically and clinically distinct from MDS and should be treated as de novo AML. Outcome in pediatric MDS remains poor, and new treatment strategies are needed for these patients.
Leukemia 1997 Feb
PMID:Myelodysplastic syndrome in children: differentiation from acute myeloid leukemia with a low blast count. 900 82

Apoptosis of hematopoietic progenitor cells is increased in myelodysplastic syndromes (MDS). We have studied Fas (CD95/Apo-1) antigen expression in 27 MDS patients (RARS 4, RA 3, RAEB 13; RAEB-t 3, CMML 4) and three AML secondary to MDS. We found that the Fas antigen was not expressed on normal bone marrow (BM) CD34+, CD14+, or glycophorin+ cells, and only slightly on CD33+ cells. Patients with MDS had upregulation of Fas expression on total bone marrow nuclear cells (BMMC) (t-test, P = 0.04), CD34+ (P = 0.013), CD33+ (P = 0.04), and glycophorin+ (P = 0.032) BM cells compared to controls. Fas expression did not correlate to the FAB subtype, the Bournemouth score, or to peripheral cytopenias. However, Fas expression intensity on CD34+ cells negatively correlated to the BM blasts number (Spearman, P = 0.01) suggesting that leukemic blasts cells lose Fas antigen expression with progression of myelodysplasia. Using both proliferation assays in liquid cultures and clonogenic progenitor assays in the presence of an agonist anti-Fas MoAb (CH11), we showed that the Fas protein was functional in some patients. Dose-dependent inhibition of DNA synthesis was observed in three out of seven patients studied. CFU-GM and BFU-E colonies suppression in some patients suggested that Fas can induce apoptosis in myeloid and erythroid BM progenitors of MDS patients. The TUNEL technique on BM smears gave a mean of 12.6% +/- 2.5 of bone marrow apoptotic cells in five controls. Patients with MDS had increased bone marrow apoptosis (mean 39% +/- 5.7, t-test, P = 0.012). Four out of 15 (26%) patients studied with a sensitive radiolabeled DNA ladder technique had typical DNA ladders indicative of advanced stages of apoptosis. Massive BM suicide was observed in patients with RA (2/2) and RAEB (8/11), whereas apoptosis rates were normal or low in patients with RAEB-t (3/3) or secondary AMLs (3/3). Moreover, high rates of apoptosis correlated to low Bournemouth score (Spearman, P = 0.01). No statistical correlation could be found between Fas expression and apoptosis rates. Our results confirm the importance of programmed cell death in MDS. The Fas antigen is clearly upregulated on BM cells, but its role in the pathophysiology of apoptosis in myelodysplasia is still unclear, indicating that many factors positively or negatively interfere with the Fas-mediated pathway of apoptosis in vivo and in vitro.
Leukemia 1997 Jun
PMID:Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. 917 38

By application of morphological and ultrastructural methods for identification of apoptosis, we analyzed the incidence of morphologically evident apoptosis in the bone marrow of 30 patients with myelodysplastic syndrome (MDS), and in the bone marrow of 12 healthy individuals. According to FAB classification, out of 30 patients, eight (26.6%) had refractory anemia, three (10%) had refractory anemia with ringed sideroblasts, 14 (46.6%) had refractory anemia with excess of blasts and two (6.8%) had refractory anemia with excess of blasts in transformation. Three patients (10%) had chronic myelomonocytic leukemia. Cells in apoptosis were examined on semithin slides and expressed as the apoptotic index (AI) (percent counted on at least 1000 cells). An overall increase in apoptosis in patients with MDS was found (median AI in patients vs controls, 3.13% vs 1.05%, P < 0.01 by Mann-Whitney U test). Also, negative correlation between AI and white blood cell count was found (linear r= -0.53, or Spearman rank R= -0.52, both P < 0.01). In patients with evident karyotype changes AI was not higher than in patients with normal karyotype. This suggests that discrete alterations in apoptosis are present even in karyotypically 'normal' clones. Our results strongly support the hypothesis that apoptosis has a role in ineffective hematopoiesis and may be a mechanism responsible for the paradox of hypercellular bone marrow and peripheral blood pancytopenia in MDS.
Leukemia 1997 May
PMID:Incidence and role of apoptosis in myelodysplastic syndrome: morphological and ultrastructural assessment. 918 Feb 88

Prognosis in patients with myelodysplastic syndromes (MDS) is closely correlated with cytopenia. To date, no factor is available which is able to reliably stimulate megakaryopoiesis in vivo. Recently, the ligand of the mpl receptor was cloned and found to be thrombopoietin (TPO). We measured endogenous TPO serum levels in 69 patients suffering from MDS using an TPO receptor-based ELISA. Twenty-six of the patients suffered from refractory anemia (RA), 12 from RA with excess of blasts (RAEB), 25 from RAEB in transition (RAEBt), and six from chronic myelomonocytic leukemia (CMML). This assay uses a chimeric molecule consisting of the human TPO receptor fused to the Fc portion of human IgG as the capture reagent. Biotinylated antibody to TPO IgG was used for detection and the lower detection limit in serum was found to be 160 pg/ml. Samples obtained from healthy individuals with a normal platelet number were shown to be below detectable levels. In patients with RA, high endogenous serum TPO concentrations correlated with low platelet count and significantly elevated TPO concentrations were only found when megakaryopoiesis was absent or decreased in the bone marrow. This correlation was not detected in RAEB and RAEBt patients and no detectable TPO serum concentrations were found in six CMML patients whether they showed decreased or normal platelet count. Our data show that endogenous TPO production is upregulated by decreased circulating platelet count only in patients with refractory anemia. In the more advanced stages of MDS where the leukemic clone has further progressed, an inadequate TPO response occurs, possibly due to overexpression of the mpl receptor by the malignant clone.
Leukemia 1998 Jan
PMID:Endogenous serum thrombopoietin concentrations in patients with myelodysplastic syndromes. 943 21

The stem cell factor (SCF)c-kit receptor interaction plays a critical role in the development and survival of mast cells. Several studies have also associated c-kit receptor mutations with the human diseases, mastocytosis and piebaldism. Overexpression of c-kit has been reported to be associated with myeloproliferative disorders and myelodysplastic syndromes. Using peripheral blood mononuclear cells (PBMCs) from 11 patients with indolent mastocytosis (category I), mastocytosis with an associated hematologic disorder (category II), or aggressive mastocytosis (category III); a patient with CMML unassociated with mastocytosis, and PBMCs from 13 normal subjects, we examined the level of expression of c-kit mRNA along with other c-kit isoforms to determine if overexpression of the c-kit receptor was associated with mastocytosis. Using quantitative competitive PCR, c-kit mRNA levels on average were found to be statistically elevated in the five patients with mastocytosis with an associated hematologic disorder and in the patient with aggressive mastocytosis as compared with controls, but not elevated in patients with indolent mastocytosis. The relative mRNA expression for the two c-kit isoforms was not significantly different in the mastocytosis patients compared with controls. This demonstration of the overexpression of c-kit mRNA in mastocytosis, and particularly those patients with clinical evidence of myelodysplastic syndrome, adds evidence to support the conclusion that mastocytosis, at least in some patients, is a feature of myelodysplasia; and suggests that determination of c-kit mRNA expression in PBMCs may provide an additional approach to assessing prognosis.
Leukemia 1998 Feb
PMID:Elevated expression of the proto-oncogene c-kit in patients with mastocytosis. 951 79

The degree of lineage commitment of the hematopoietic stem cell in chronic myelomonocytic leukemia (CMML) and in acute myelogenous leukemia (AML) remains debatable and may be heterogeneous depending on the patient subgroup. In this study, we have used a modification of DNA in situ hybridization which adapts this technique to the analysis of karyotype in single hematopoietic colonies. By utilizing a digoxigenin-labeled chromosome 7 probe, we demonstrate that, in patients with monosomy 7, both erythroid and myelomonocytic progenitors can be karyotypically aberrant. In addition, significant levels of diploid clonogenic cells persist (as reflected by the presence of between 14% and 43% diploid colonies) despite the detection of only monosomy 7-bearing bone marrow metaphases as assessed by standard cytogenetic techniques. Our observations demonstrate that digoxigenin-based DNA in situ hybridization (DISH) can be performed on individually microaspirated colonies for determination of lineage derivation. This technique may also be applicable to the detection of minimal residual disease with clonogenic potential and for assessing the interaction between normal and leukemic precursors.
Leukemia 1998 Feb
PMID:DNA in situ hybridization of individual colonies to determine lineage derivation in leukemia. 951 89

The molecular mechanisms underlying the development and evolution of myelodysplastic syndrome (MDS) are largely unknown. The increasing number of blast cells in the bone marrow correlate with poor prognosis and risk of developing acute leukemia. Such progression is frequently associated with increasing chromosomal abnormalities and genetic mutations. A cohort of 75 MDS patients were investigated for RAS, FMS and p53 mutations, and these molecular findings were related to cytogenetics, clinical status, transformation to acute leukemia, prognostic scores and survival. A mutation incidence of 57% (43/75) was found, with 48% (36/75) RAS mutations, 12% (9/75) FMS mutations and 8% (4/50) p53 mutations. The mutation status for RAS and FMS was related to MDS subgroup, increasing with poor-risk disease. The highest incidence was in the chronic myelomonocytic leukemia (CMML) subgroup. The most frequent RAS mutations were of codon 12 and a predominance of FMS codon 969 mutations was observed. A statistically significant increased frequency of transformation to AML was observed in MDS patients harboring RAS or FMS mutations (P < 0.02). Patients with oncogene mutations had a significantly poorer survival compared with those without mutations at 2 years and at the end of the period of follow-up (P < 0.02). Multivariate analysis including mutation, age, gender, diagnosis (FAB), cytogenetics and International score shows that the International score and mutation and age is the best predictive model of a poor outcome, (P < 0.0001). When the analysis was undertaken without the International score, mutation and gender was the best predictor of poor survival (P = 0.005). This study shows that oncogene mutation, indicative of genetic instability, is associated with disease progression and poor survival in MDS.
Leukemia 1998 Jun
PMID:RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. 963 16

Involvement of the ETV6 gene, located at 12p13, has been investigated in 20 patients with an abnormality of the short arm of chromosome 12 (abn 12p) detected cytogenetically. Patients in the study had c/pre-B acute lymphoblastic leukemia (ALL) (nine children and three adults), T-ALL (three adults), acute myeloid leukemia (AML) (two adults), biphenotypic acute leukemia (Bip-L) (one adult), myelodysplasia (MDS) (one adult) and chronic myelomonocytic leukemia (CMML) (one child). Abnormalities of 12p comprised deleted (del)(12p) alone (seven cases), add(12p) alone (seven cases), del(12p) and add(12p) (one case) and balanced translocations of 12p to 1p13, 1q31, 10q11, 14q11 and 15q15 (one case of each). A novel, exon-specific RT-PCR assay identified breakpoints in ETV6 in nine of 19 cases, and showed breakpoints in intron 5 (seven cases of children with c-ALL), in intron 4 (in one adult with Bip-L) and in intron 2 (in one adult with AML). RT-PCR for the ETV6/AMLI fusion (tested in 19 cases) was positive using standard primers in five cases (four of which had shown rearrangements in intron 5) and occurred as a variant fusion in a sixth case (also positive for a rearrangement in intron 5) using 3' RACE PCR. Southern blotting confirmed rearrangements in intron 5 in the five cases available for analysis and revealed a rearrangement in intron 5 in one of 10 cases with no evidence of intron 5 involvement by RT-PCR. Rearrangements in intron 5 of ETV6 were found in eight of nine cases of children with c-ALL of which six carried the ETV6/AMLI fusion. Heterozygosity within intron 5 (revealed by the genomic probe B1) was found in seven of 11 cases tested. Deletion of one allele was indicated in three cases with del(12p) and one case with add(12p). This study, using a combination of ETV6 exon-specific RT-PCR, RT-PCR for ETV6/AMLI and Southern blotting has shown that rearrangement and/or deletion of ETV6 may occur in up to 70% of patients with abn 12p. Furthermore, 90% of children in this study with an abn 12p and c-ALL, carried a rearrangement of ETV6 in intron 5.
Leukemia 1998 Jul
PMID:Abnormalities of the ETV6 gene occur in the majority of patients with aberrations of the short arm of chromosome 12: a combined PCR and Southern blotting analysis. 966 96

Fourty children with MDS treated in seven centres of The Polish Children's Leukemia Lymphoma Study Group in period 1975-1998y were included to the study. In 16 children RAEB-T, in 2 CMML in 10 RA and in 12 RAEB were diagnosed. Our and literature data showed that BMT is the best therapy for children with MDS. For children, who don't have a donor for BMT. Roacutan therapy seems to be the most effective.
 ...
PMID:[Treatment outcome for myelodysplastic syndromes (MDS) obtained by the Polish Children's Leukemia/Lymphoma Study Group]. 968 18


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