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PubMed1998

Expression of bomapin, a novel human serpin, in normal/malignant hematopoiesis and in the monocytic cell lines THP-1 and AML-193.

Our group recently cloned the cDNA-encoding bomapin, a member of the serine protease inhibitor (serpin) superfamily, from a human bone marrow cDNA library (J Biol Chem 270:2675, 1995). To understand its expression within the hematopoietic compartment, RNA extracted from bone marrow or peripheral blood from normal donors and patients with leukemia was reverse transcribed and analyzed by polymerase chain reaction (PCR). Bomapin PCR products were readily detected in normal bone marrow, which was designated as a medium mRNA level. In peripheral blood, bomapin expression was low or undetectable in normal donors (n = 6) and patients with chronic lymphocytic leukemia (n = 6). Blood from patients with chronic myeloid leukemia (n = 6), chronic myelomonocytic leukemia (n = 6), acute myeloid leukemia (n = 5), and acute lymphocytic leukemia (n = 5) exhibited low to medium levels of bomapin expression. Furthermore, a high level of bomapin expression was detected in one individual with acute monocytic leukemia. These data suggest that bomapin expression may be elevated in hematopoietic cells of monocytic lineage. Therefore, we analyzed the expression of bomapin within cell lines that exhibited characteristics of the monocytic lineage. Bomapin PCR products were detected in the monocytic THP-1 and AML-193 cell lines but not in CRL 7607, CRL 7541, KG-1, or K562 cells. Induction of bomapin transcripts was not detected in the latter series of cell lines following a 24-hour treatment with phorbol myristate acetate (PMA, 10(-8) mol/L) or tumor necrosis factor-alpha (TNF-alpha, 30 U/mL), whereas treatment of THP-1 or AML-193 cells with these agents reduced the intensity of the bomapin PCR products. Northern blotting confirmed these results and showed that the expression of bomapin in THP-1 cells was downregulated over a 4-day period by PMA and, to a lesser extent, TNF-alpha. Immunoblotting was used to show the presence of a 40-kD protein in THP-1 cytosol preparations. Bomapin antigen levels were correspondingly reduced after treatment with PMA. Because PMA and TNF-alpha induce monocytic differentiation in THP-1 and AML-193 cells, these data increase the possibility that bomapin may play a role in the regulation of protease activities specifically in early stages of cellular differentiation.

Cell Differentiation↗

PubMed1998

Increased levels of a chromosome 21-encoded tumour invasion and metastasis factor (TIAM1) mRNA in bone marrow of Down syndrome children during the acute phase of AML(M7).

Children with Down syndrome (DS) have a 10-20-fold increased risk of acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), compared to non-DS children. The myeloid leukemia that accounts for nearly 50% of DS leukemias is usually the otherwise uncommon megakaryoblastic type (AML-M7). Though an etiological role of trisomy 21 in leukemogenesis has been suggested, the expression of genes on chromosome 21 in relation to trisomy, DS, and specific DS phenotypes such as leukemia is poorly understood. We used a heterologous-mimic competitive RT-PCR technique to measure the mRNA levels of a chromosome 21 tumour invasion and metastasis factor (TIAM1) directly in bone marrow samples of DS leukemic patients. In the limited number of cases analysed so far, we found TIAM1 mRNA levels in the DS AML-M7 samples of bone marrow taken in the acute phase of the disease (presentation or relapse, n=8) to be highly significantly raised, nearly threefold, compared to that measured in the remission samples or normal individuals (normals + remissions, n=10).

Acute Disease↗

PubMed2005

A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia: the Japan Adult Leukemia Study Group AML 97 Study.

BACKGROUND: A major concern in the treatment of patients with acute myeloid leukemia (AML) is how to prevent disease recurrences. Although intensive consolidation therapy has proven useful, the effectiveness of maintenance therapy remains controversial. METHODS: Seven hundred eighty-nine patients ages 15-64 (median: 45 yrs) with de novo AML received induction therapy, which consisted of cytosine arabinoside (at a dose of 100 mg/m(2) on Days 1-7) and idarubicin (at a dose of 12 mg/m(2) on Days 1-3). The patients who achieved complete remission (CR) were then randomized into groups that received either four courses of standard-dose consolidation therapy without maintenance (Arm A) or three courses of standard-dose consolidation and six courses of maintenance therapy (Arm B). RESULTS: In total, 78.7% of patients achieved CR. The 5-year overall survival (OS) rate for the 789 eligible patients was 46.9%, and the disease-free survival (DFS) rate for the 621 patients who achieved CR was 32.9%. The 5-year OS rate for Arm A was 52.4%, and 58.4% for Arm B (P = 0.599). The 5-year DFS rate for the patients who achieved CR was 35.8% in Arm A and 30.4% in Arm B (P = 0.543). In analyzing the data according to the risk groups, no statistical difference was observed either in the 5-year OS rate or in the 5-year DFS rate between the 2 arms. CONCLUSIONS: In the current study, the Japan Adult Leukemia Study Group's conventional postremission therapy (three courses of standard-dose consolidation and six courses of maintenance therapy) was replaced successfully by a shorter duration of four courses of standard-dose consolidation therapy without the need for additional maintenance therapy.

Adolescent↗

PubMed2002

Up-front randomization and common standard arm: a proposal for comparing AML treatment strategies between different studies.

Most multicenter randomized AML studies use randomizations of patients early or later in complete remission which necessarily occur with exclusions and positive selection of patients included. Since the exclusion criterias are regimen related and do not follow common standards, incomparabilities between treatment results across different studies are produced by these late randomizations. In order to overcome this problem, we here propose a cooperation of studies on the basis of a general up-front randomization with attribution of 10% patients from each study to a common standard arm. A validation of complete treatment strategies according to intent-to-treat against the standard arm and thus also across the studies is provided by this inter-group model which may contribute to accelerate the therapeutic progress in AML.

Acute Disease↗

PubMed2004

A new prognostic score for patients with acute myeloid leukemia based on cytogenetics and early blast clearance in trials of the German AML Cooperative Group.

BACKGROUND AND OBJECTIVES: To refine cytogenetically based risk-stratification in acute myeloid leukemia (AML). DESIGN AND METHODS: Stratification was improved by combining cytogenetics and day 16 bone marrow blasts and by subdividing unfavorable cytogenetics. The new score identifying five prognostically different groups was developed in 321 patients (AMLCG 1992 trial) and subsequently validated in 680 patients (AMLCG 1999 trial). RESULTS: Subgroups defined were: 1) favorable cytogenetics (t(8;21), inv(16)); 2) intermediate cytogenetics (normal karyotype, other abnormalities not rated favorable or unfavorable) and day 16 blasts <10%; 3) intermediate cytogenetics and day 16 blasts >or=10%; 4) unfavorable cytogenetics (-5/5q-, -7/7q-, 3q21q26 aberrations, 11q23 aberrations, 12p-, 17p-) excluding complex aberrations; 5) complex aberrant karyotypes (>or=3 aberrations). In AMLCG 1992 patients significant differences were observed with regard to complete remission (CR) rate (82%, 83%, 58%, 76%, 53%), persistent leukemia (PL) rate (7%, 8%, 33%, 14%, 31%), median event-free survival (EFS; 25, 14, 5, 6, 2 months), median overall survival (OS; not reached, 26, 12, 14, 6 months), and median relapse-free survival (RFS; 26, 19, 13, 8, 4 months). The prospective validation of the score proved its significant power (AMLCG 1999 cohort) with regard to CR (63%, 65%, 51%, 45%, 35%), PL (17%, 18%, 40%, 35%, 48%), median EFS (14, 7, 3, 2, 2 months), median OS (25, 15, 12, 6, 4 months), and median RFS (not reached, 15, 10, 8, 5 months). INTERPRETATION AND CONCLUSIONS: This new prognostic score provides a highly valuable tool for future clinical trials in AML focusing on distinct and subgroup-specific treatment effects.

Acute Disease↗

PubMed1999

Severe adverse impact on sexual functioning and fertility of bone marrow transplantation, either allogeneic or autologous, compared with consolidation chemotherapy alone: analysis of the MRC AML 10 trial.

BACKGROUND: Data relating to the impact of bone marrow transplantation (BMT) on sexual functioning are equivocal; some studies have shown no major impact whereas others demonstrate a significant adverse effect on sexual health in patients treated with BMT. Further clarification is required to facilitate treatment choices and follow-up management of patients. METHODS: A cross-sectional study of sexual health and infertility was conducted in 479 patients with acute myeloid leukemia (AML) in first complete remission (CR) who were entered into the UK MRC AML 10 trial comparing allogeneic BMT (Allo-BMT), autologous BMT (A-BMT), and intensive consolidation chemotherapy (CCT). Assessment was made by patient questionnaire via the treating centers for completion and returned directly to the coordinating center. RESULTS: Both Allo-BMT and A-BMT were observed to have severe, highly significant adverse effects on the patients' sexual health. Significantly more BMT patients than CCT patients reported a decrease in interest in sex (48% vs. 24%), sexual activity (53% vs. 35%), pleasure from sex (36% vs. 18%), and ability to have sex (38% vs. 18%) (P < 0.001 in each case). Hormonal disorders and infertility also were more common in BMT patients than in CCT patients. These differences were more apparent in women and remained after adjustment for age. CONCLUSIONS: These results indicate a need to consider quality of life parameters when reviewing treatment options and to instigate effective proactive management strategies for dealing with sexual health problems in leukemia survivors.

Acute Disease↗

PubMed1998

Rearrangement between the MYH11 gene at 16p13 and D12S158 at 12p13 in a case of acute myeloid leukemia M1 (AML-M1).

A case of acute myeloid leukemia (AML) M1 with bone marrow eosinophilia was characterized by cytogenetics and fluorescence in situ hybridization (FISH). A complex karyotype including a der(12)t(12;17)(p12-13;q11) and a der(16)t(16;20)(p13;p11) was found at diagnosis. FISH studies with probes for chromosome 16 and for the short arm of chromosome 12 showed even more complex rearrangements. Analysis with a panel of probes for 12p showed that D12S158 spanned the breakpoint on the der(12). Unexpectedly, FISH signals were found on the der(12) and on the der(6) at band p13, the site of juxtaposition between the short arm of chromosome 16 and chromosome 20. Moreover, both YAC 854E2, containing the MYH11 gene, and cosmid ZIT133, encompassing the MYH11 breakpoint in inv(16) and t(16;16) of AML-M4 with eosinophilia, demonstrated fluorescent signals on the normal 16, on the der(16), and on the der(12). These data clearly support a reciprocal exchange between D12S158 at 12p13.3 and the MYH11 gene at 16p13. In addition, experiments with two PAC clones for the CBFB gene at 16q22 excluded the presence of a masked inv(16). An interstitial deletion, independent from the translocation and flanked by VWF and KRAS2, was also detected on the der(12).

Aged↗

PubMed2000

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an important treatment modality for children with AML. The optimal conditioning regimen is unknown. The aim of this study was to determine the appropriate dosing of etoposide in combination with busulfan and cyclophosphamide in this setting. PROCEDURE: Twenty patients with a diagnosis of AML in first or second remission, or myelodysplasia scheduled for bone marrow transplantation, were included in this study. Patients received busulfan 640 mg/m(2) in 16 doses, cyclophosphamide 120 to 150 mg/kg in two doses, and etoposide from 40-60 mg/kg as a single dose. Extensive toxicity data was collected. RESULTS: Nineteen patients were evaluable for toxicity. Mucositis was seen in all patients. Four patients developed bacteremia and one patient died from overwhelming sepsis on day +3. Four patients developed moderate to severe skin toxicity. The major dose-limiting +3 toxicity was hepatic toxicity, which occurred in 14 of 19 patients. Eight patients developed clinical veno-occlusive disease, including three patients at dose level 4, two of whom had life-threatening disease. This hepatic toxicity defined the MTD of 640 mg/m(2) busulfan, 120 mg/kg of cyclophosphamide, and 60 mg/kg of etoposide. Overall, 9 of 20 patients enrolled in the study survive in remission, 8/14 allogeneic (median follow-up 44 months), and one of six autologous patients (follow-up, 54 months). CONCLUSIONS: We conclude that the combination of busulfan, cyclophosphamide, and etoposide at the doses defined above has activity in the treatment of children with high-risk AML/MDS undergoing allogeneic HSCT. Whether it offers an advantage over other conditioning regimens will require a randomized trial with a larger cohort of patients.

Adolescent↗

PubMed1976

The chromosomes and causation of human cancer and leukemia. XVIII. The missing Y in acute myeloblastic leukemia (AML) and Ph1-positive chronic myelocytic leukemia (CML).

The occurrence of a missing Y chromosome was investigated in the bone marrow cells of male individuals, i.e., 255 controls, 73 with acute myelocytic leukemia (AML) and 59 with Ph1-positive chronic myelocytic leukemia (CML). The incidence in controls of individuals with 45,X cells increased with age, particularly after the age of 60. In AML, 45,X metaphases were detected in two patients over 70 years of age, but the leukemia seemed to have involved the 46,XY cells rather than the 45,X cells. Four of the six patients with No. 8-No. 21 translocation and two of the 16 with major karyotypic abnormalities (MAKA) exhibited a missing Y in the leukemic cells in addition to other karyotypic aberrations. Four of the Ph1-positive CML patients exhibited a missing Y in all or nearly all the cells in the bone marrow along with the Ph1. In one patient, additional chromosome abnormalities involved the 46,XY,Ph1 rather than the 45,X,Ph1 cells. The genesis of the missing Y in CML cells may be related to the presence of the Ph1, though apparently the patient's age also plays a role. It is our hypothesis that 45,X or 45,X,Ph1 cells are resistant to the development of further chromosomal abnormalities and, thus, reflect their resistance to being involved in an acute leukemic process.

Adolescent↗

PubMed1979

Chromosomes and causation of human cancer and leukemia. XXXII. Unusual features of Ph1-positive acute myeloblastic leukemia (AML), including a review of the literature.

Five cases of Ph1-positive AML were studied. In all cases a Ph1-chromosome was shown with banding techniques to be due to a translocation between chromosomes No. 9 and No. 22. Cases 1 and 4 were found to have more than one Ph1 with evidence of only on Ph1-translocation accompanying other chromosome abnormalities. Two cases represented an unusual pattern of appearance and disappearance of the Ph1-positive clone during their clinical courses: Case No. 2 was originally Ph1-positive (46,XY,Ph1) but two months before his expiration the Ph1-positive clone was completely replaced by a newly developed Ph1-negative clone with an abnormal chromosome No. 21 (46,XY,21q+), whereas case No. 3, primarily Ph1-negative, developed a Ph1-positive clone among the previously karyotypically normal cells one month before death. The Ph1-positive AML cases presented have been discussed in relation to: 1) the genesis and significance of the Ph1-positive clone, 2) differentiation from the blastic phase of CML and 31 the general experience with Ph1-positive acute non-lymphocytic leukemia (ANLL), the world literature of which have been tabulated.

Adolescent↗

PubMed1980

High rate of long-term survivals in AML treated by chemotherapy and androgenotherapy: a pilot study.

An unexpectedly high rate of long-term survivors in acute myeloid leukemia (AML) has been observed in a group of patients who achieved a first complete remission (CR) after induction of a therapeutic regimen including daunorubidomycine, vincristine, prednisone and stanozolol, and anabolizing steroid. The rate of CR was 52%. Maintenance therapy was very simple and the only association with stanozolol during this period suggested to us that an androgen, at low dosages, might be responsible for the unusual long-term survival time (45 months with a 95% confidence limit from 30 to 86 months). On the basis of our first observation, high dosages of the androgen were used during the induction phase of treatment but failed to demonstrate any advantage when associated with a drug regimen, including cytosine arabinoside (ARA-C). The reevaluation of each parameter for our group of patients did not allow selection of patients in terms of their age or the hematologic data obtained at presentation. Effects of androgen on the socalled normal hemopoietic cells and on the leukemic cells are discussed, particularly the possible antagonistic effect with ARA-C. A prospective statement is made concerning the possible condition of the prolongation of the complete remission in AML according to some experimental data which enforce the stimulative activity of androgen on the myeloid proliferation.

Adolescent↗

PubMed1984

Transplantation of non-purified autologous bone marrow in patients with AML in first remission.

Four patients with acute myeloid leukemia (AML) were treated with high-dose cyclophosphamide and total body irradiation followed by reinfusion of a portion of their own bone marrow collected during remission. This procedure was applied when the patients were in complete remission. They did not receive further maintenance chemotherapy after grafting. The use of bone marrow for grafting that had been pre-exposed to high-dose chemotherapy for remission induction did not preclude good hematologic regeneration. All patients showed stable remissions that lasted for 64+, 21, 40+, and 19+ months, respectively. Death in the second patient was due to a medullary relapse of the leukemia. Autologous bone marrow transplantation in patients with AML in remission may permit lasting remissions, even when applied without additional chemotherapy and attempts to purify the marrow of neoplastic cells.

Adolescent↗

PubMed1993

Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensification therapy between 4 or 12 courses in adult acute myeloid leukemia. AML-87 Study of the Japan Adult Leukemia Study Group.

BACKGROUND: It was assessed whether addition of vincristine (VCR) to remission induction therapy would increase the complete remission (CR) rate, and, secondarily, whether 12 courses of maintenance-intensification therapy would produce longer survival than 4 courses in adult acute myeloid leukemia (AML). METHODS: A randomized comparison of individualized induction therapy was conducted between daunorubicin, behenoyl cytarabine, 6-mercaptopurine, and prednisolone with or without VCR. After 3 courses of intensive consolidation therapy, maintenance-intensification therapy was randomized to 4 or 12 courses given every 6 weeks. RESULTS: Of 265 patients registered, 252 were evaluable. CR was obtained in 78%; 80% in 205 patients of age younger than 60 years, and 65% in 47 of age 60 years or older. Addition of VCR reduced the CR rate significantly (84% to 70%, P = 0.007). Predicted 4-year survival, continuing CR, and disease-free survival (DFS) rates of 196 CR patients are 45%, 41%, and 35%, respectively. Patients receiving 12 courses of maintenance-intensification showed better DFS. By multivariate analyses, significant factors for achievement of CR were performance status 0 to 2, age younger than 60 years, and no VCR; and those for longer DFS were achievement of CR by one course, age younger than 50 years, and French-American-British (FAB) classification M3 or M5. Among 131 patients randomized to the maintenance, the administration of 12 courses was the most important factor (P = 0.0040) for longer DFS, followed by FAB M3 or M5, and by achievement of CR by one course. CONCLUSIONS: Addition of VCR in remission induction therapy was harmful, and longer intensive maintenance therapy prolonged DFS in adult AML.

Acute Disease↗

PubMed2000

Differential display as an approach to study differentiation and differentiation therapy in AML.

Different subgroups of acute myeloid leukemia (AML) can be defined by the specific non-random chromosomal translocation that is present within the abnormal cell types. In one type of AML, acute promyelocytic leukemia (APL), the block in the normal process of differentiation can be circumvented by the addition of a chemical inducer, in this case retinoic acid. This is due to the defect in APL affecting the retinoic acid receptor gene. This type of therapy has become known as differentiation therapy. However, most types of leukemia do not respond to the retinoic acid, and therefore methods of differentiation therapy need to be developed by targeting other genes involved in the leukemia process. This requires the molecular characterizations of the genes that are expressed during differentiation and in particular those genes that show a differential expression in inducer sensitive cells and those resistant to induced differentiation. Therefore, therapeutic agents could be developed to specifically target these genes. This article describes how the technique of differential display, as one of several possible methods of molecular screening, may allow the identification of genes which can be targeted to induce differentiation.

Acute Disease↗

PubMed2001

IL-1beta down-regulates tissue-type plasminogen activator by up-regulating low-density lipoprotein receptor-related protein in AML 12 cells.

Interleukin-1 (IL-1) regulation of tPA in hepatocytes was studied in mouse hepatocyte line AML12. IL-1 induced transient accumulation of tPA mRNA as high as threefold by 2 h after the start of treatment. The cytokine also induced the mRNA for serum amyloid A, a typical acute-phase protein in mice, with more sustained kinetics in a time-dependent manner. In contrast to the induction of mRNA, tPA activity and protein levels in the harvested medium were dramatically diminished by IL-1. IL-1 stimulated the uptake of (125)I-tPA by AML 12. This uptake was inhibited by 39-kDa receptor-associated protein (RAP), but not by the sugar mannan. These results revealed that low-density lipoprotein receptor-related protein (LRP), which is known to be a receptor for tPA and to be blocked by RAP, was up-regulated by IL-1. We also demonstrated, for the first time, that IL-1 transiently increased the mRNA level of LRP threefold by 30 min after the start of IL-1 treatment of AML 12. The receptor-mediated endocytosis of tPA by hepatocytes may thus play a crucial role in the down-regulation of fibrinolysis during the acute-phase response.

Animals↗

PubMed1999

AML-M0: a review of laboratory features and proposal of new diagnostic criteria.

In 1991, the FAB group published a proposal to designate acute leukemias with minimal signs of myeloid differentiation as AML-M0. This proposal was meant to offer a provisional basis for the study of immature myeloid forms, with the understanding that it was susceptible to changes and improvements with new information derived from the laboratory. Since then there have been a number of reports detailing the biological and clinical features of patients with AML-M0. In this article we review the laboratory data acquired from various sources and suggest a partial modification of diagnostic criteria.

Acute Disease↗

PubMed1998

Preliminary crystallographic study of glutathione S-transferase fused with the nuclear matrix targeting signal of the transcription factor AML-1/CBF-alpha2.

A glutathione S-transferase fused with the nuclear matrix targeting signal (GST-NMTS) of AML-1/CBF-alpha2 has been crystallized by the vapor diffusion method using polyethylene glycol (PEG) as the precipitant. The NMTS is a 31-amino-acid signal peptide that can target the AML-1/CBF-alpha2 protein to the nuclear matrix. The crystal belongs to tetragonal space group P43212 with unit cell dimensions a = b = 93.4 A, c = 57.6 A. There is one GST-fusion protein per asymmetric unit. Crystals diffracted to at least 2.7 A and are appropriate for structure determination.

Animals↗

PubMed1999

Both Pgp and MRP1 activities using calcein-AM contribute to drug resistance in AML.

Thirteen cell lines with different levels of Pgp and MRP1 expression were used to assess the ability of calcein-AM uptake and calcein efflux to measure Pgp and MRP1 functions, respectively. There was a good correlation between MRP1 expression and the modulatory effect of probenecid (a specific modulator of MRP1) on the calcein efflux (r = 0.91, p = 0.0003) and between Pgp expression and the modulatory effect of CsA on calcein-AM uptake (r = 0.96, p < 0.0001). On light of the high correlations for both proteins, we tested calcein-AM uptake and efflux in fresh myeloid leukemic cells. In 53 AML patients, there was also a good correlation between MRP1 expression (measured by RT/PCR and by MRPm6 expression by flow cytometry) and the modulatory effect of probenecid on the calcein fluorescence (r = 0.92, p < 0.0001) and between Pgp expression as measured by UIC2 antibody binding on flow cytometry and the modulatory effect of CsA on calcein-AM uptake (r = 0.83, p < 0.0001). Pgp activity was higher in CD34+ leukemia than in CD34- leukemia (2.26 +/- 1.50 vs 1.46 +/- 1.21 respectively, p = 0.003) and MRP1 activity was higher in CD34- leukemia than in CD34+ leukemia (1.77 +/- 0.40 vs 1.4 +/- 0.29 respectively, p = 0.004). Pgp expression and activity (p = 0.004 and p = 0.01, respectively), MRP1 activity (p = 0.03) but not MRP1 expression were prognostic factors for achievement of CR. The effect of probenecid and CsA together were higher than the effect of either probenecid or CsA alone on calcein-AM uptake. These results suggest that functional testing (with calcein-AM +/- modulators) for the presence of both MRP1 and Pgp activities is of prognostic value and that MRP1 contributes to drug resistance in AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗