AF17q25, a putative septin family gene, fuses the MLL gene in acute myeloid leukemia with t(11;17)(q23;q25).
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The t(11;17) has been described in patients with acute myeloid leukemia (AML), and the AF17 gene was previously cloned as a fusion partner of the MLL gene in t(11;17)(q23;q21)-AML. We analyzed one patient with de novo AML and one with therapy-related AML with t(11;17)(q23;q25) and identified the AF17q25 gene on chromosome 17q25, a putative septin family gene, fused with MLL. AF17q25 encoded at least three kinds of proteins [type I (568 a.a.), type II (594 a.a.), and type III (574 a.a.)] that contained two kinds of different amino acid sequences at the COOH terminus. The MLL-AF17q25 fusion transcript consisted of type I AF17q25 transcript. The AF17q25 protein is homologous to septin family proteins, including H5, NEDD5, CDC10, and hCDCrel, which is one of the fusion partners of MLL in t(11;22)(q23;q11)-AML. These results suggest that AF17q25 and hCDCrel might define a new septin family particularly involved in the pathogenesis of 11q23-associated leukemia. (+info)
Myelodysplastic syndrome that progressed to acute myelomonocytic leukemia with eosinophilia showing peculiar chromosomal abnormality: a case report.
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Myelodysplastic syndrome is a closely related group of acquired bone marrow disorders characterized by ineffective and dysplastic hematopoiesis. These clonal disorders frequently progress to acute leukemia. Acute myelomonocytic leukemia with eosinophilia is characterized by an increase in abnormal eosinophils in the bone marrow, relatively good clinical course and inv (16) chromosomal abnormality. We experienced one case of refractory anemia with excess blasts which progressed to refractory anemia with excess blasts in transformation and finally to acute myelomonocytic leukemia with eosinophilia showing peculiar chromosomal abnormalities of der (1;7). (+info)
Chromosomal instability in acute myelocytic leukemia and myelodysplastic syndrome patients among atomic bomb survivors.
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To clarify the mechanism of leukemogenesis in atomic bomb survivors, leukemic cells were investigated using fluorescence in situ hybridization (FISH) analysis on the basis of conventional G-banding in patients with a history of radiation exposure and also in de novo patients. Conventional G-banding showed higher incidences (p < 0.005) of structural and numerical abnormalities without any specific types of chromosome aberrations in the group exposed to a dose of more than one Gy, compared to the non-exposed group. FISH analysis revealed significantly higher incidences (P < 0.05) of subclones with monosomy 7 and deletion of the 20q13.2 region, which were not found in conventional cytogenetic analysis in the exposed group (more than one Gy) compared to the non-exposed controls. Furthermore, segmental jumping translocation (SJT) of the c-MYC gene region was observed only in the exposed group. These chromosomal instability suggested that the leukemic cells from the heavily exposed patients contained persistent cellular genetic instability which may strongly influence the development of leukemia in people exposed to radiation. (+info)
Triggering noncycling hematopoietic progenitors and leukemic blasts to proliferate increases anthracycline retention and toxicity by downregulating multidrug resistance.
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Expression of the multidrug resistance (MDR) mechanisms P-glycoprotein (Pgp) and MDR-related protein (MRP) decrease cellular retention and consequently cytotoxicity of anthracyclines. MDR is expressed on normal human hematopoietic progenitors and leukemic blasts. Normal CD34(+) progenitors showed rhodamine efflux in 20% to 30% of the cells, which could be blocked by verapamil. These cells appeared noncycling, in contrast to the proliferating rhodamine bright (RhoB) cells. We postulated that MDR expression can be downregulated by proliferation induction. Triggering rhodamine dull (RhoD) CD34(+) cells to proliferate indeed resulted in a higher rhodamine retention and significantly decreased efflux modulation by verapamil (P =.04). Also in acute myeloid leukemia (AML), the proliferation rate (percentage S/G(2)+M and Iododeoxyuridine labelings index) was significantly less in the RhoD blasts (P +info)
p15(INK4B) CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing.
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The promoter region of the cyclin-dependent kinase inhibitor p15(INK4B) contains a CpG island that is hypermethylated in many hematologic malignancies. To explore the relationship between patterns of methylation and gene transcription, we used bisulfite genomic sequencing to obtain a detailed analysis of methylation in acute leukemia, leukemia cell lines, and normal lymphocytes. The entire CpG island region of p15 was largely devoid of methylation in normal lymphocytes, but methylation of varying density was found in primary acute leukemia. Methylation density was generally conserved between the alleles from each sample, but marked heterogeneity for the specific CpG sites methylated was observed. Patterns of methylation were compared and expression assessed with reverse-transcriptase polymerase chain reaction (RT-PCR). The density of methylation within the CpG island, and not any specific location, correlates best with transcriptional loss. Leukemias with methylation of approximately 40% of the CpG dinucleotides on each allele had complete gene silencing, with variable, but diminished expression with less dense CpG island methylation. Our results suggest that the transcriptional silencing of p15 in conjunction with aberrant hypermethylation is best understood as an evolutionary process that involves progressively increasing methylation of the entire p15 CpG island. (+info)
Biochemical pharmacology and resistance to 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, a novel analogue of cladribine in human leukemic cells.
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The objective of the present study was to investigate the biochemical pharmacology of 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA)--a fluorinated analogue of cladribine [2-chloro-2'-deoxyadenosine, Leustatin (CdA)] with improved acid and metabolic stability--in human leukemic cell lines and in mononuclear cells isolated from patients with chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML). We have also made and characterized two cell lines that are not sensitive to the growth inhibitory and cytotoxic effects of CAFdA. Incubation of cells isolated from the blood of CLL and AML patients with various concentrations of CdA or of CAFdA accumulated CdA and CAFdA nucleotides in a dose-dependent manner. A significantly higher rate of phosphorylation to monophosphates was observed for CAFdA than for CdA in cells from CLL patients (n = 14; P = 0.04). The differences in the phosphorylation were even more pronounced for the respective triphosphates in both CLL (n = 14; P = 0.001) and AML (n = 4; P = 0.04) cells. Retention of CAFdA 5'-triphosphate (CAFdATP) was also longer than that for CdA 5'-triphosphate (CdATP) in cells from leukemic patients. The relative efficacy of CAFdA as a substrate for purified recombinant deoxycytidine kinase (dCK), the key enzyme in the activation of nucleoside analogues, was very high and exceeded that of CdA as well as the natural substrate, deoxycytidine, by a factor of 2 and 8, respectively. The Km for CAFdA with dCK was also lower than that for CdA, as measured in crude extracts from the human acute lymphoblastic leukemia cell line CCRF-CEM and the promyelocytic leukemia cell line HL60. Acquired resistance to CAFdA in HL60 and in CCRF-CEM cell lines was directly correlated to the decreased activity of the nucleoside phosphorylating enzyme, dCK. Resistant cells also showed a considerable degree of cross-resistance to analogues that were activated by dCK. These observations demonstrated that dCK phosphorylates CAFdA more efficiently than CdA. Furthermore, CAFdATP is apparently more stable than CdATP and the mechanisms of resistance to CAFdA are similar to those leading to CdA resistance. These results encourage studies on the clinical effect of CAFdA in lymphoproliferative diseases. (+info)
Acute myelogenous leukemia after treatment for malignant germ cell tumors in children.
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PURPOSE: To identify the long-term sequelae of therapy for malignant germ cell tumors (GCTs). PATIENTS AND METHODS: Between 1980 and 1998, 1,132 patients were prospectively enrolled onto the German nontesticular GCT studies. A total of 442 patients received chemotherapy using combinations of the drugs cisplatin, ifosfamide, etoposide, vinblastine, and bleomycin, and 174 patients were treated with a combination of chemotherapy and radiotherapy. Median follow-up duration was 38 months (range, 6 to 199 months). RESULTS: Six patients developed therapy-related acute myelogenous leukemia (t-AML). There was no t-AML among patients treated with surgery (n = 392) or radiotherapy only (n = 124). The Kaplan-Meier estimates of the cumulative incidence (at 10 years) of t-AML were 1.0% for patients treated with chemotherapy (three of 442) and 4.2% for patients treated with combined chemotherapy and radiotherapy (three of 174). Notably, four of these six patients had been treated according to a standard protocol with modest cumulative chemotherapy doses. Five patients had received less than 2 g/m(2) epipodophyllotoxins, and four patients had received less than 20 g/m(2) ifosfamide. Four patients presented with AML, two with myelodysplasia in transformation to AML. In five patients, cytogenetic aberrations were found, four of which were considered characteristic for t-AML. Four patients died despite antileukemic therapy. One patient is alive but suffered a relapse of his GCT, and one patient is alive and well. No secondary solid neoplasm was observed. CONCLUSION: In patients with AML after treatment for GCT, several pathogenetic mechanisms must be considered. AML might evolve from a malignant transformation of GCT components without any influence of the chemotherapy. On the other hand, the use of alkylators and topoisomerase II inhibitors is associated with an increased risk of t-AML. Future studies will show if the reduction of treatment intensity in the current protocol reduces the risk of secondary leukemia in these patients. (+info)
Bone marrow transplantation for therapy-induced acute myeloid leukemia in children with previous lymphoid malignancies.
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Twenty-one children who developed therapy-related acute myeloid leukemia after treatment for acute lymphoblastic leukemia received allogeneic bone marrow transplants between January 1990 and June 1997. All had previously received epipodophyllotoxin-containing regimens and 11 had cytogenetic abnormalities involving 11q23. Induction chemotherapy was given to 13 patients and eight patients went directly to BMT. Eleven received marrow from matched siblings, eight from matched unrelated donors and two from haploidentical family members. Conditioning regimens included cyclophosphamide (CY), cytarabine, and total body irradiation. Four patients are alive disease-free between 1118 and 1825 days post-BMT resulting in a 3-year DFS of 19%. Ten patients relapsed at a median of 150 days (range 30-664 days) post-BMT and all eventually died of disease. Seven patients died of regimen-related toxicity. The outlook for patients with therapy-related AML/MDS remains poor and more effective therapy is needed. (+info)