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

Deletions of the long arm of chromosome 5 with common overlapping segment 5q31.1 are among the most frequent cytogenetic aberrations in myelodysplastic syndromes and acute myeloid leukemias (MDS/AML). We have constructed a YAC-based physical map of the 5q31.1 critical locus and localized the transcriptional transactivator Smad5 adjacent to loci showing consistent loss of heterozygosity in these disorders. Smad5 plays a key role along the bone morphogenetic protein-4 (BMP-4) inhibitory signalling pathway inducing embryonic hematopoiesis. Smad5 homologs Smad2 and DPC4 have recently been linked to human cancer. FISH analysis of AML-M2 cell line HL60 and of four MDS/AML patients revealed consistent hemizygous loss of the Smad5 locus. In HL60 cells, a translocation event within 5q31.1 associated with loss of adjacent material leads to disruption of the critical locus with partial retention of the 5q31.1 genomic sequences on a marker chromosome. RT-PCR sequencing analysis of the HL60 Smad5 remaining allele ruled out the functional inactivation of the gene analogous to that occurring in the Smad5 homologs DPC4 and Smad2 in cases of pancreatic and colorectal cancers. Mutational analysis of Smad5 in MDS/AML cases is in progress.
Leukemia 1997 Aug
PMID:Smad5, a tumor suppressor candidate at 5q31.1, is hemizygously lost and not mutated in the retained allele in human leukemia cell line HL60. 926 67

Thirty-five patients, 24 males and 11 females, with myelodysplastic syndromes were studied for the expression of c-myc encoded p67 oncoprotein. According to FAB classification, 5 patients had refractory anaemia (RA). 5 refractory anaemia with ringed sideroblasts (RARS), 17 refractory anaemia with excess of blasts (RAEB), 4 refractory anaemia with excess of blasts in transformation (RAEB-t), and 4 chronic myelomonocytic leukaemia (CMML). The mouse anti-human 9E10 derived monoclonal antibody in the standard APAAP technique for immunohistochemical analysis was used. A scoring method similar to that routinely used for endogenous neutrophil alkaline phosphatase estimation, was applied to obtain parametrically comparable results. In all but two MDS patients, the observed c-myc oncoprotein score values did not differ statistically from those found in the controls. The values did not correlate with peripheral blood or bone marrow blast cell numbers. In two out of 17 patients with RAEB in whom very high c-myc score values were found, acute non-lymphocytic leukaemia (ANLL) was diagnosed 30 and 45 days later, respectively. Furthermore, we found high c-myc score values in three patients with RAEB and in two patients with RAEB-t during the ANLL phase which was diagnosed six to ten months after the initial study. Our data suggest that c-myc activation may be seen in all cases of MDS in overt ANLL phase, and also in some RAEB patients a few weeks before diagnosis of overt ANLL. The possible prognostic value of c-myc activation in MDS patients remains to be clarified.
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PMID:Increased expression of c-myc p67 oncoprotein in patients with myelodysplastic syndromes in transformation to acute leukaemia. 928 97

A quantitative analysis of expression levels of GM-CSF receptors was performed by flow cytometry in different disease categories, ie AML (n = 72), ALL (n = 18), and MDS (n = 12), as well as 12 healthy volunteers, using three different unconjugated GM-CSF/R monoclonal antibodies (McAbs) (HGM-CSFR (CD116), M5D12, 4B5F5), and appropriate standards. By using the reference HGM-CSFR McAb, in healthy subjects we found detectable levels of GM-CSF/R on blood monocytes (mean MESF (molecules of equivalent soluble fluorochrome)/cell: 36.1 x 10[3]), neutrophils (mean MESF/cell: 7.4 x 10[3]), bone marrow (BM) myelo-monocytic precursors (MESF range for the myeloid component, ie promyelocytes, myelocytes, metamyelocytes: 11.7-40.5 x 10[3], and for the monocytic lineage: 25.7-69.2 x 10[3]), and in two distinct subsets of BM CD34+ progenitor cells (GM-CSF/R dim: 2.5 x 10[3] MESF/cell, GM-CSF/R bright (10% of the total number of CD34 cells: 22.0 x 10[3] MESF/cell). In these subjects, there was no correlation between the expression levels of GM-CSF/R and CFU (CFU-GM, CFU-GEMM, BFU-E) colony production. Among the AML samples, M5D12 McAb was positive in 33%, 4B5F5 McAb in 90%, and HGM-CSF/R McAb in 78% of the cases examined (range of MESF/cell for the HGM-CSFR McAb: 0.9 x 10[3]-106.7 x 10[3]). The highest MESF values were seen in the M5 FAB subvariety (mean: 39.4 x 10[3]), where all the patients tested (n = 20) showed a strong positivity for the HGM-CSFR McAb. On the contrary, all ALL samples were GM-CSF/R negative except in two patients, who displayed a dim GM-CSF/R positivity (My+ALL: 1.3 x 10[3] MESF/cell; pro-B ALL: 1.0 x 10[3] MESF/cell). In most (>70%) M1 FAB subtypes, GM-CSF/R+ blasts co-expressed CD34low, HLA-DRhigh, CD33, CD38 antigens, and had little or no capacity to form CFU-GM colonies. GM-CSF/R+ blasts from the M5 FAB category were also positive for CD14, CD11c, CD33 and CD87. Furthermore, the number of GM-CSF/R expressed by leukemic cells from five out of 72 (7%) AML patients was above the highest values seen in normal samples (>69.2 x 10[3] MESF/cell), allowing the possibility of using this marker for the monitoring of the minimal residual disease (MRD) in a subset of AML. Cell culture studies aimed at evaluating GM-CSF receptor modulation following AML blast exposure to rhGM-CSF showed two distinct patterns of response; in the first group (6/10 cases) rhGM-CSF down-modulated GM-CSF receptors, whereas in the second group (4/10 cases), rhGM-CSF treatment was associated with either an increase or no change in the number of GM-CSF/R. In conclusion, cellular GM-CSF/R expression was variable and ranged from undetectable (ALL and a minority of AML) to very high intensities in M5 AML, and were also documented in some M0 AML, thus suggesting the concept that GM-CSF/R detection may be of help in lineage assignment of undifferentiated forms. Since the number of GM-CSF/R on AML blasts may be modulated after GM-CSF treatment, it can be postulated that the clinical use of GM-CSF in this disease may be optimized by a dynamic analysis of the number and the affinity status of GM-CSF-R in blasts and normal hemopoietic cells.
Leukemia 1997 Oct
PMID:Flow cytometry measurement of GM-CSF receptors in acute leukemic blasts, and normal hemopoietic cells. 932 92

We evaluated the in vitro effects of IL-12, alone and in association with IL-2 on MDS bone marrow and peripheral blood cells. Thirty-six patients and 14 healthy subjects were studied. Natural killer-activity (NK-a) levels and lymphocyte immunophenotypes were determined in fresh bone marrow (BMMNC) and peripheral blood mononuclear cells (PBMNC), which then were resuspended in medium containing IL-2, IL-12 or IL-2 + IL-12 for 7 days. Re-evaluation of NK-a levels, lymphocyte immunophenotypes, clonogenic activity and cytokine release showed that, unlike IL-2, IL-12 did not significantly increase NK-a or CD3-/56+ cell levels in either bone marrow or peripheral blood; IL-2 + 12 led to a significant increase that fell between the values reached by each cytokine alone. IL-2 + 12 and, although to a lesser extent, also IL-12 alone induced the release of large amounts of gamma-IFN and alpha-TNF. In addition, the number of clusters particularly decreased in the samples treated with IL-2 + 12 and IL-12 alone. Clonogenic activity was not modified after stimulation with any of the treatment. These data suggest that IL-12 induces the release of inhibitory cytokines in normal as well as MDS cells and that it could be used in patients with elevated bone marrow blastosis.
Leukemia 1997 Oct
PMID:In vitro effects of IL-12 and IL-2 on NK cells, cytokine release and clonogenic activity in myelodysplastic syndromes (MDS). 932 94

We have investigated a case of acute myelocytic leukaemia derived from myelodysplastic syndrome (MDS-AML) with an 8;21 translocation. In this case the AML1/MTG8 (ETO) fusion transcript was not detected by reverse transcriptase-polymerase chain reaction (RT-PCR), and the rearrangement of the AML1 gene locus was not detected by Southern blot nor pulse field gel electrophoresis (PFGE) analyses using specific probes for the AML1 gene. Fluorescence in-situ hybridization (FISH) study using cosmid probes for 21q22 revealed that the breakpoint of 21q22 was telomeric to the AML1 gene locus and centromeric from D21S259, 351, 3421 loci. This is the first report concerning the t(8;21)(q22;q22) carrying AMLs (de novo AML, MDS-AML and therapy-related AML) to show that the breakpoint at 21q22 is located outside the AML1 gene locus. It is also noteworthy that the cell-surface antigen expression pattern of the bone marrow (BM) blasts was changed from CD7+ CD2+ CD13+ CD33+ CD19- CD11b+ CD14+ CD36+ to CD7- CD2- CD13+ CD19+ CD11b- CD14- CD33+ CD34+ CD36- CD56+ during leukaemic progression, and the pattern in leukaemic phase was similar to the characteristic phenotype of de novo AML cases with t(8;21), when the AML1/MTG8 fusion transcripts are always detected by RT-PCR.
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PMID:Genetic analysis of 8;21 chromosomal translocation without AML1 gene involvement in MDS-AML. 940 Oct 77

A pharmacokinetic study of all-trans retinoic acid (ATRA) was performed in 8 patients with various types of leukemia and MDS. After oral administration at a dose of 30 mg/m2, the mean peak plasma concentration was 430 ng/ml and was reached at 150 min. In one patient who failed to respond a very low plasma ATRA level was seen. Though the plasma ATRA exposure decreased significantly with daily drug administration, an intermittent schedule of ATRA administration would yield higher plasma drug concentrations. We treated 2 patients with refractory acute promyelocytic leukemia (APL) in a pilot study of ATRA followed by intensive chemotherapy (APL-ATRA protocol). Two patients successfully achieved complete remission with ATRA after failing under conventional chemotherapy. Based on the pharmacokinetic study of ATRA, an intermittent schedule of ATRA in addition to chemotherapy suggests an effective regimen for children with APL. Phase II trials to evaluate the role of intermittent schedules of ATRA are planned in Children's Cancer and Leukemia Study Group.
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PMID:[Pharmacokinetic studies of all-trans retinoic acid (ATRA) and pilot study of intermittent schedule of ATRA and chemotherapy in childhood acute promyelocytic leukemia. Children's Cancer and Leukemia Study Group]. 942 33

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

Therapy-related leukemia and myelodysplastic syndrome (TRL/MDS) in Japan were analysed in a multi-institution study to assess clinical, cytogenetic aspects, and prognostic factor. From 1985 to 1994, 405 cases of adult TRL/MDS were diagnosed and overall percentage of TRL/MDS in leukemia and MDS was 1.9%. Median age was 61 years old. The median latency from primary malignancies was 53.4 months, which latency was significantly shorter in the patients treated with chemotherapy. Primary malignancies were hematologic in 39%. Common symptoms were fatigue/ weakness and anemia. Chromosome 7,5, and 11 were frequently involved. MLL gene rearrangement were detected in 12 of 64 analysed cases. Overall median survival was 10.0 months. Body weight loss, neurologic abnormality, hypoproteinemia, hypofibrinogenemia, proteinuria, lack of Auer rods, and 5q-were prognostic factors in TRL/MDS. This large population study documented some datas useful for the prevention of TRL/MDS.
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PMID:[Therapy-related leukemia and myelodysplastic syndrome: a multi-institution study in Japan]. 946 95

The mechanism of benzene toxicity has been extremely difficult to fully characterize. Much progress has been made in assessing the relative potency of benzene metabolites but specific pathways to leukemia remain to be determined. Metabolite and mechanistic studies will have to focus on aplastic anemia and MDS and separate endpoints. This may serve to clarify the array of metabolite effects and consequent disparate effects. Biomarker research can contribute to the understanding of the toxicity process. The significance of understanding benzene toxicity will also lead to better clinical treatment of aplastic anemia and therapy-related MDS and AML, detection of populations particularly susceptible to benzene toxicity, screening of populations with suspected or unknown exposures, and determination of meaningful values for occupational and individual health risk while effectively monitoring ongoing exposures for early signs of toxicity.
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PMID:Scientific update on benzene. 947 33

Secondary leukaemia has rarely been reported as a complication of autologous stem cell transplantation for AML. We report two cases of AML who presented with well-characterised cytogenetic abnormalities at presentation: t(8;21) and t(15;17) respectively, and who, after achieving complete morphological and cytogenetic remissions post-autograft, developed MDS/AML associated with monosomy 7. This secondary change is most frequently seen following alkylating agent therapy for solid tumours. The secondary leukaemia seen in our patients may thus be due to exposure of the residual stem cells to the alkylating agents used in the transplant conditioning.
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PMID:Secondary leukaemia characterised by monosomy 7 occurring post-autologous stem cell transplantation for AML. 960 16


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