Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor alpha (TNFalpha) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFalpha monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.
 ...
PMID:Inhibition of granulocyte-macrophage colony-stimulating factor prevents dissemination and induces remission of juvenile myelomonocytic leukemia in engrafted immunodeficient mice. 938 8

Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disease of early childhood, that is peculiarly characterized by the ability of bone marrow progenitors to spontaneously proliferate in vitro, giving rise to granulocyte-macrophage colonies. Although the genetic alteration/s leading to JMML development are still unclear, several lines of evidence indicate that the JMML initiating cell (JMML-IC) may belong to the pool of early stem-like hematopoietic progenitors. Increased EVI-1 gene expression has been detected in a number of myeloproliferative disorders including MDS, AML, blast crisis of CML, and more recently in the peripheral blood of some JMML patients. In order to investigate the nature of the cells expressing EVI-1 in JMML patients, we analyzed its expression in CFU-GM obtained from bone marrow and peripheral blood as well as from highly purified CD34+ progenitors. Normal CFU-GM obtained both from bone marrow mononuclear cells and from highly purified CD34+ cells were also analyzed. Overall, our results suggest that the EVI-1 gene may be normally expressed in early hematopoietic progenitor cells and that in JMML patients an expansion of the EVI-1 positive cell population can be revealed within the clonogenic progenitor pool.
Leukemia 1997 Dec
PMID:EVI-1 gene expression in myeloid clonogenic cells from juvenile myelomonocytic leukemia (JMML). 944 18

It has been unclear whether a graft-versus-leukemia (GVL) effect assists in the control of juvenile myelomonocytic leukemia (JMML) following allogeneic bone marrow transplant. We describe a patient with JMML who relapsed early after an unrelated donor transplant, and following withdrawal of immunosuppression developed graft-versus-host disease (GVHD). Associated with GVHD the proportion of donor cells measured by variable nucleotide tandem repeat (VNTR) analysis increased, and peripheral blasts and cutaneous disease were eliminated. These findings strongly suggest that GVL has a role in the control of JMML.
 ...
PMID:Graft-versus-leukemia is sufficient to induce remission in juvenile myelomonocytic leukemia. 970 31

To investigate a genetic relation between juvenile chronic myelogenous leukemia (JCML) and neurofibromatosis type 1 (NF-1), we analyzed the NF1 gene in the leukemic cells of a JCML patient with NF-1. We found a point mutation in exon 29 of one allele and a deletion of the other normal allele in the leukemic cells. The point mutation is considered a germline mutation because it was also detected in fibroblasts obtained from the bone marrow of the patient and the peripheral blood mononuclear cells from a sibling. A loss of heterozygosity of NF1 gene may contribute to the progression of leukemia in NF-1 patients.
 ...
PMID:Loss of heterozygosity of NF1 gene in juvenile chronic myelogenous leukemia with neurofibromatosis type 1. 971 68

We have previously demonstrated that human granulocyte-macrophage colony-stimulating factor fused to a truncated diphtheria toxin (DT388-GM-CSF) is toxic to patient acute myeloid leukemia progenitors bearing the GM-CSF receptor, but not normal marrow progenitors. We now report that exposure of mononuclear cells from five of seven (71%) juvenile myelomonocytic leukemia (JMML) patients and from 12 of 20 (60%) adult chronic myelomonocytic leukemia (CMML) patients to 10(-9) mol/L DT388-GM-CSF for 48 hours in culture reduces the number of cells capable of forming colonies in semisolid medium (colony-forming units-leukemia) 10-fold to 300-fold (1 to 2.5 log decrease). In contrast, normal myeloid progenitors (colony-forming unit-granulocyte-macrophage) from six different donors treated and assayed under identical conditions were consistently insensitive to the same fusion toxin even when treated as highly purified CD34(+) cells. The leukemic progenitors from the two other JMML patients showed intermediate sensitivity to DT388-GM-CSF and the leukemic progenitors from eight of the 20 (40%) CMML patients were not different from normal progenitors. Parallel measurements of the number and affinity of GM-CSF receptors on cells from the same samples showed no consistent differences between JMML, CMML, and normal light density or CD34(+) bone marrow cells. The increased sensitivity of leukemic progenitors from all JMML progenitors and some CMML patients to the fusion toxin is therefore not likely to be explained by an increased density of GM-CSF receptors on these cells. We also examined the DT388-GM-CSF sensitivity of two murine cell lines transfected with cDNAs encoding varying portions of the human GM-CSF receptor and/or beta chains. These studies showed that high-affinity ligand binding was sufficient for DT388-GM-CSF-induced toxicity, as this could occur even in the absence of functional signal transduction and that the background of the host cell had a major influence on the degree to which this decreased the toxicity of DT388-GM-CSF. The selective sensitivity to DT388-GM-CSF of leukemic progenitors from a majority of JMML and CMML patients suggests that this agent could have therapeutic potential for some patients with these diseases.
 ...
PMID:Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor is toxic to blasts from patients with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. 983 34

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder of early childhood with excessive proliferation of the myeloid and monocytic lineage. Deregulation of the RAS signal transduction pathway is thought to play a key role in its pathogenesis. We examined peripheral blood or bone marrow cells of 36 children with JMML for activating point mutations in codons 12, 13 and 61 of the NRAS and KRAS proto-oncogenes by allele-specific restriction assay, single-strand conformation polymorphism and/or direct sequencing. Codons 12, 13 and 61 of HRAS were examined in 26 of these patients. We detected RAS mutations in six cases (17%) located at N12 (n = 2), N13 (n = 3) and K13 (n = 1). In addition, we performed clonality studies on different cell lineages in four of these patients applying the RAS mutation, the karyotype and X-chromosome inactivation patterns as clonal markers. Erythroid cells carried mutant RAS, indicating clonal origin. In EBV B cell lines, one of three patients studied harbored a RAS mutation, while the other two patients had polyclonal B cells with wild-type RAS. T lymphocytes were examined in one patient; they were polyclonal and had wild-type RAS. It is likely that JMML is a heterogeneous disease with respect to clonal involvement of different lineages.
Leukemia 1999 Jan
PMID:RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). 1004 57

The triple association of leukemia, xanthomatous skin lesions, and neurofibromatosis 1 (NF) was first described by Royer et al. in 1958. Most of the leukemias were of the juvenile chronic myelogenous type (JCML). We describe a 7-year-old male child with xanthoma, neurofibromatosis 1, and juvenile chronic myelogenous leukemia. His mother also had NF1. We suggest that the presence of xanthomas and NF1 in a young child should raise awareness of the possible development of JCML, especially in patients with a family history of NF1.
 ...
PMID:Juvenile chronic myelogenous leukemia, neurofibromatosis 1, and xanthoma. 1006 10

We reviewed the clinical features, treatment, and outcome of 100 children with myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML) associated with complete monosomy 7 (-7) or deletion of the long arm of chromosome 7 (7q-). Patients with therapy-induced disease were excluded. The morphologic diagnoses according to modified FAB criteria were: MDS in 72 (refractory anemia (RA) in 11, RA with excess of blasts (RAEB) in eight, RAEB in transformation (RAEB-T) in 10, JMML in 43), and AML in 28. The median age at presentation was 2.8 years (range 2 months to 15 years), being lowest in JMML (1.1 year). Loss of chromosome 7 as the sole cytogenetic abnormality was observed in 75% of those with MDS compared with 32% of those with AML. Predisposing conditions (including familial MDS/AML) were found in 20%. Three-year survival was 82% in RA, 63% in RAEB, 45% in JMML, 34% in AML, and 8% in RAEB-T. Children with -7 alone had a superior survival than those with other cytogenetic abnormalities: this was solely due to a better survival in MDS (3-year survival 56 vs 24%). The reverse was found in AML (3-year survival 13% in -7 alone vs 44% in other cytogenetic groups). Stable disease for several years was documented in more than half the patients with RA or RAEB. Patients with RA, RAEB or JMML treated with bone marrow transplantation (BMT) without prior chemotherapy had a 3-year survival of 73%. The morphologic diagnosis was the strongest prognostic factor. Only patients with a diagnosis of JMML fitted what has previously been referred to as the monosomy 7 syndrome. Our data give no support to the concept of monosomy 7 as a distinct syndrome.
Leukemia 1999 Mar
PMID:Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS). 1008 28

A 12 year-old girl with juvenile myelomonocytic leukemia (JMML) and monosomy 7 underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. To monitor the engraftment and the course of the disease we used fluorescence in situ hybridization (FISH) with probes specific for the centromeres of chromosomes X, Y and 7. Complete hematological remission was achieved and confirmed by the virtually exclusive presence of normal male cells in the bone marrow (BM). Acute graft-versus host disease (GvHD) was treated with prednisone and cyclosporine A (CSA) and female cells with monosomy 7 reoccurred in the peripheral blood (PB) and BM. After discontinuation of the immunosuppressive therapy, the leukemic cells with monosomy 7 disappeared again from these compartments. One year after transplantation, isolated extramedullary relapses occurred in lymph nodes and skin, followed by dissemination of blast cells into the BM, whereas the PB cells remained of donor origin. The fact that the leukemic cells fluctuated with the intensity of the immunosuppressive treatment provides evidence of a graft versus leukemia (GvL) effect in this unusually old girl with JMML with a unique extramedullary disease progression.
 ...
PMID:Extramedullary relapse despite graft-versus-leukemia effect after bone marrow transplantation in a girl with juvenile myelomonocytic leukemia. 1034 89

Juvenile chronic myelomonocytic leukaemia (JMML) is a rare myeloproliferative disorder of childhood. Fewer than 30% of cases of JMML terminate in a blast crisis; however, its molecular mechanism is unknown. Since mutation and/or deletion of the p53 gene has been reported to be associated with disease progression in a wide variety of human cancers, including adult-type chronic myelogenous leukaemia, we studied the p53 gene in 20 patients with JMML (16 samples in chronic phase and seven at blast crisis). Exons 4-8 of the p53 gene, which cover all the hot spots of point mutations, were amplified by the polymerase chain reaction (PCR) method and subjected to mutation screening by single-strand conformation polymorphism analysis. No mobility shift of single-strand DNA of PCR products in polyacrylamide gel electrophoresis, indicating point mutations, was found in 19/20 patients. DNA of the remaining patient in the chronic phase failed to be amplified by PCR and Southern blot analysis with XbaI-digested genomic DNA revealed a gross rearrangement (presumed deletion) of the p53 gene. These data indicate that abnormalities of the p53 gene are rare in JMML and not responsible for acute transformation, but could be involved in the pathogenesis of some cases of JMML.
 ...
PMID:Abnormalities of the p53 gene in juvenile myelomonocytic leukaemia. 1052 1


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