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PubMed2005

Activation of HLXB9 by juxtaposition with MYB via formation of t(6;7)(q23;q36) in an AML-M4 cell line (GDM-1).

Mutation or dysregulation of related homeobox genes occurs in leukemia. Using RT-PCR, we screened members of the EHG family of homeobox genes, comprising EN1 (at 2q14), GBX2 (at 2q36), and EN2, GBX1, and HLXB9 (at 7q36), for dysregulation in acute myeloid leukemia (AML) cell lines indicated by chromosomal breakpoints at these sites. Only one EHG-family gene was expressed, HLXB9, in cell line GDM-1 (AML-M4). Karyotypic analysis of GDM-1 revealed a unique t(6;7)(q23;q35), also present in the patient. Fluorescence in situ hybridization analysis showed chromosomal breakpoints close to the region upstream of HLXB9, at 7q36, a region rearranged in certain AML patients, and at 6q23 upstream of MYB, a gene activated in leukemia. Detailed expression analysis suggested ectopic activation of HLXB9 occurred via juxtaposition with regions upstream of MYB, which was highly expressed in GDM-1. Our data identified a cell line model for a novel leukemic translocation involving MYB with HLXB9, further implicating HLXB9 in leukemogenesis.

Cell Line, Tumor↗

PubMed2005

Centromeric breakage and highly rearranged chromosome derivatives associated with mutations of TP53 are common in therapy-related MDS and AML after therapy with alkylating agents: an M-FISH study.

Multicolor fluorescence in situ hybridization (M-FISH) was performed on bone marrow cells of 116 unselected cases of therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML), and the results were compared with those of previously performed with G-banding. Among 18 patients with a normal karyotype, no cryptic chromosome aberrations were observed with M-FISH. In 56 patients with a previously solved abnormal karyotype, only 17 new aberrations were identified, whereas 153 new aberrations were detected by M-FISH in 42 patients with a previously unsolved karyotype. In total, 112 of the new aberrations were unbalanced translocations, and only nine were balanced translocations. A clustering of breakpoints was observed in the centromeric or pericentromeric region of chromosomes 1, 5, 7, 13, 17, 21, and 22 in 48 of 98 patients with t-MDS and t-AML and an abnormal karyotype, and was related to previous therapy with alkylating agents. In seven of eight patients with chromosome derivatives containing material from three or more chromosomes or having sandwichlike chromosomes, those made up of several small interchanging layers of material from two chromosomes showed mutations of TP53. M-FISH had little impact on the prognostic classification of t-MDS and t-AML, as only three patients changed prognostic groups as a result of M-FISH.

Acute Disease↗

PubMedDate not supplied

Acute myelogenous leukemia (AML) and diabetes insipidus (DI): further association with monosomy 7.

Diabetes insipidus (DI) is a rare complication of acute myelogenous leukemia (AML). Five of the six such cases described in the literature who had banded chromosomal studies performed had monosomy 7 and the sixth patient had del(7)(q22). A further case of AML complicated by DI in whom banded chromosomal studies revealed a complex karyotypic abnormality, including monosomy 7, is reported. The association between monosomy 7 and DI in AML appears specific but the reason for this association remains unclear.

Chromosomes, Human, Pair 7↗

PubMed2006

Leukemogenic AML1-ETO fusion protein upregulates expression of connexin 43: the role in AML 1-ETO-induced growth arrest in leukemic cells.

AML1-ETO, a fusion protein generated by the chromosomal translocation t(8;21), is frequently associated with acute myeloid leukemia (AML). In addition to blocking differentiation, AML1-ETO is also shown to induce growth arrest in AML cells, which is unfavorable for leukemogenesis harboring the t(8;21) translocation. However, its precise mechanism is still unclear. Here we provide the first demonstration that the conditional expression of AML1-ETO by the ecdysone-inducible system dramatically increases the expression of connexin 43 (CX43), together with growth arrest at G1 phase in leukemic U937 cells. We also show that the CX43 induction inhibits the proliferation of U937 cells at G1 phase, while the suppression of CX43 expression by small interfering RNA (siRNA) effectively overcomes the growth-inhibitory effect of AML1 -ETO in leukemic cells. Furthermore, either AML1-ETO or CX43 induction elevates cell-cycle negative regulator P27(kip1) protein by inhibiting its degradation, which is antagonized by siRNA against CX43. Taken together, our data indicate that CX43 plays a role in AML1-ETO-induced growth arrest possibly through the accumulation of P27(kip1) protein. The potential mutation or/and epigenetic alterations of CX43 and its related gene(s) deserve to be explored in AML1-ETO-positive AML patients.

Base Sequence↗

PubMed2005

Allogeneic versus autologous versus peripheral stem cell transplantation in CR1 pediatric AML patients: a single center experience.

BACKGROUND: Treatment of childhood acute myelocytic leukemia (AML) in first remission, is still evolving. Allogeneic bone marrow transplantation (BMT) in patients with a donor has been well established, but the role of autologous transplantation remains of interest, particularly in the light of some encouraging results in adults. PROCEDURE: Out of 81 pediatric patients with AML in first CR, 67 were biologically randomized for allogeneic (n = 31), autologous (n = 20), or peripheral stem cell transplant (n = 16) after completing consolidation treatment, with the remaining (n = 11) dropping out or receiving chemotherapy. Disease free survival (DFS) of these different groups were analyzed. RESULTS: Allogeneic transplantation is not superior to autologous and autologous peripheral blood stem cell transplantation (PBSCT) (DFS in 5 years is 61%, 50%, and 75%). The 5 years DFS in the autologous PBSCT group is significantly better than in the autologous BMT group (75% vs. 50%, P < 0.05). CONCLUSION: In pediatric AML patients without a donor, autologous BMT or autologous PBSCT appears to be an effective treatment option with low transplant related mortality especially in less privileged countries where the chemotherapy only results are still low.

Acute Disease↗

PubMed2006

Curing childhood acute myeloid leukemia (AML) at the half-way point: promises to keep and miles to go before we sleep.

Childhood and adolescent acute myeloid leukemia (AML) is traditionally one of the hardest childhood cancers to successfully treat and had an overall survival well under 10% in the 1960s. Initial progress was made by three major events: (1) active chemotherapeutic agents were identified which led to remissions for the first time in this disease; (2) cooperative groups were instituted leading to important clinical trials; and (3) several single institutions began experimenting with the role of allogeneic matched sibling donor (MSD) BMT as effective intensification. Over the last 25 years, the cure rate has improved from <20% to 50% or higher. Most of the clinical research during this time of great advancement focused on two major themes: (1) the role of aggressive induction therapy in not only improving CR rates but in post-remission outcomes; and (2) the role of aggressive post-remission therapy in further improving survival, with an emphasis on high-dose Ara C-based chemotherapy, BMT, and supportive care. But we have "miles to go before we sleep." Some of the challenges that will lead to ongoing reduction of population-based mortality for AML through young adulthood include: (1) improving access of adolescents to pediatric AML therapy; (2) stratification by prognostic factors; (3) individualized therapy based on individual genetics and leukemia cell biology; (4) and the use of novel therapies including targeted immuno-conjugates and "small molecules" which disrupt abnormal signal transduction pathways. This brief review looks at both the advances over the last three decades as well as discusses the challenges moving forward for ultimately curing all children with this disease.

Acute Disease↗

PubMed1980

Use of the AML scale to identify adjustment problems in fourth-, fifth-, and sixth-grade children.

This paper summarizes a series of studies of the technical merit of the AML scale when used to detect school maladaptation in a sample of 684 fourth, fifth, and sixth-grade children. Teachers, who did the rating, readily accepted this screening device. Preliminary norms are offered. Reliability and factor analytic studies show a reasonable degree of uniqueness and internal consistency among the three AML subscales. Relationships to other children's personality and behavioral indices (State-Trait Anxiety Inventory for Children and Cooper-smith's Self-Esteem Inventory) were found to be modest. The one-item L Scale correlated well (r = .65) with the California Achievement Test. First developed as a measure of school maladaptation in primary grade youngsters, the AML appears to be readily applicable at intermediate grade levels as well.

Age Factors↗

PubMed2002

Prognosis of elderly patients with acute myelogenous leukemia: analysis of 126 AML cases.

We retrospectively analyzed 126 acute myelogenous leukemia (AML) patients aged > or =60 years who had all been referred to the same hematological department between 1989 and 1999. In 76 de novo AML cases, 53 patients (median age, 72 years) were treated with combination chemotherapy (CT) for remission induction. Complete remission (CR) rate was 57.1%. The median overall survival (OS) was 16 months, and the rate of 3-year OS was 28%. The favorable prognostic factors were performance status < or =2, cholinesterase > or =100 IU, and intermediate or favorable karyotype (P < .01). Seventeen patients (median age, 78 years) with hypocellular bone marrow or poor general condition were treated with low-dose cytosine arabinoside (LDAraC). In these patients, the CR rate was 50% and the median OS was 11 months, with an OS estimate at 3 years of 14%. All patients with hypocellular bone marrow who received LDAraC for 21 days achieved CR. In 50 patients who developed AML following a myelodysplastic syndrome (MDS/AML), 22 patients (median age, 74 years) were treated with CT, and 14 (median age, 74 years) patients were treated with LDAraC. The CR rates were 22.7% and 21.4%, respectively, and the median OS durations were 8 months and 11 months, respectively. There were no significant factors that would indicate a good prognosis in MDS/AML patients.

Acute Disease↗

PubMed1993

Induction of cytotoxic lymphocyte subsets against leukemia by stimulation with AML blasts.

Although the application of interleukin-2 (IL-2) activated lymphocytes in immunotherapy of acute myelogenous leukemia (AML) is of therapeutic interest, the high resistance of AML blasts to lymphocyte lysis may represent an obstacle to this type of therapy. However, our data shows that the leukemia resistance can be conquered by concomitant culture of lymphocytes with IL-2 and AML blasts. This approach induces not only leukemia-directed cytotoxic cells, but also promotes their growth. Additionally, multiple cytotoxic lymphocyte populations with leukemia lytic activity are induced in AML/IL-2 cultures. These include natural killer (NK) cells and subsets of T cells with both the major histocompatibility complex (MHC)-restricted and MHC-nonrestricted cytotoxic function. Thus, this protocol, which is conducive to general stimulation of cellular immune responses against leukemia, may enhance the benefits of lymphocyte therapy.

Humans↗

PubMed2000

Secondary acute myeloblastic leukaemia (AML) (expressing 11q23 mutation) occurring 11 months after chemotherapy/radiotherapy for paediatric non-Hodgkin lymphoma (NHL).

The occurrence of 11q23 cytogenetic abnormalities in drug-induced acute myeloid leukaemia (AML) is now well recognized. They are most frequently associated with topoisomerase II inhibitor administration. We here describe the case history of a 15-year-old child who presented with Stage III B-cell non-Hodgkin's lymphoma (NHL) and was treated with anthracyclines, alkylating agents and low-dose mediastinal radiotherapy. She developed an 11q23 mutation-related secondary AML at 11 months after therapy (15 months after her first exposure to drugs; 12 months after the first radiotherapy exposure), possibly the earliest yet reported in a paediatric patient. We discuss this newly recognized early form of refractory, secondary AML and its relationship to chemoradiotherapy.

Adolescent↗

PubMed2003

High-risk AML complicated by pulmonary aspergillosis: successful treatment with nonmyeloablative stem cell transplantation and long-term administration of voriconazole.

Acute myeloid leukemia (AML) associated with central diabetes insipidus (DI) and chromosomal aberrations is characterised by a very poor prognosis. We present a 28-year-old female with AML FAB M0, preceding DI and cytogenetic abnormalities (monosomy 7 and inversion of chromosome 9). Complete remission was achieved with FLAG after she was refractory to two different induction regimens. Prolonged neutropenia resulted in invasive pulmonary aspergillosis. Allogeneic stem cell transplantation from a matched unrelated donor was performed using a reduced-intensity conditioning regimen. Desmopressin substitution for DI was withdrawn after transplant without recurrence of symptoms. Initial antifungal treatment, including liposomal amphotericin B, caspofungin and itraconazole, was replaced by voriconazole after deterioration of pulmonary aspergillosis, resulting in improvement, stabilisation and finally, also as the combined effect of discontinuation of the immunosuppressive therapy, in disappearance of signs and symptoms. Thirteen months after transplant, the patient is in continuous complete remission. The presented case study thus demonstrates that high-risk AML with concomitant invasive fungal infection may be safely and effectively treated by nonmyeloablative stem cell transplantation and long-term administration of voriconazole.

Adult↗

PubMed1996

Paraneoplastic hypokalemia in acute myeloid leukemia: a case of renin activity in AML blast cells.

Hypokalemia due to renal potassium loss has frequently been observed in patients with acute myeloid leukemia (AML). The pathogenic mechanism for this hyperkaluresis is unclear. In this report we describe a patient with AML FAB M4, in whom the clinical course, the electrolyte disturbances, the serum aldosterone levels, and the diffuse hyperplasia of the adrenal cortex documented a typical case of marked secondary hyperaldosteronism. On analysis of the leukemic cells of this patient compared with normal bone marrow cells, a significant increase of renin-like activity in the cytosol of the blast cells was noted. Activation of the renin-angiotensin-aldosterone system by paraneoplastic production of renin-like activity in AML blast cells might contribute to the hypokalemia often observed in patients with acute myeloid leukemia.

Acute Disease↗

PubMed1998

Granulocyte colony-stimulating factor shortens duration of critical neutropenia and prolongs disease-free survival after sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy for refractory and relapsed acute myeloid leukemia. German AML Cooperative Group.

Patients with primary refractory or relapsed acute myeloid leukemia (AML) who undergo intensive salvage chemotherapy carry a high risk of treatment failure due to infectious complications and early relapses. The study presented here assessed the effect of granulocyte colony-stimulating factor (G-CSF) on the duration of post-treatment neutropenia, the incidence of infection-related deaths, and the disease-free and overall survival. Sixty-eight evaluable patients with relapsed and refractory AML received G-CSF 5 microg/kg per day subcutaneously starting 2 days after the completion of salvage treatment with the S-HAM regimen, consisting of high-dose cytosine arabinoside twice daily on days 1, 2, 8, and 9 and mitoxantrone on days 3, 4, 10, and 11. Ninety-one patients who were treated with the identical S-HAM regimen but without G-CSF support during a preceding study served as controls. The application of G-CSF resulted in a significant shortening of critical neutropenia of less than 500 microl (36 vs. 40 days; p = 0.008), which translated into a trend towards a lower early death rate (21% vs. 30%) and an increase of complete remissions (56% vs. 47%, p=0.11). In patients younger than 60 years a significant prolongation of time to treatment failure (159 vs. 93 days, p=0.038) and of duration of disease-free survival (203 vs. 97 days, p=0.003) was observed. These results indicate a beneficial effect of G-CSF on early mortality as well as on long-term outcome when administered after S-HAM salvage therapy for advanced AML.

Acute Disease↗

PubMed1991

Doxorubicin and m-AMSA induced DNA damage in blast cells from AML patients.

We investigated m-AMSA or doxorubicin (Dx) induced DNA single-strand breaks (DNA-SSB) in myeloid leukemia cells obtained from 8 adult patients suffering from AML. Highly purified AML cells were stimulated to proliferate with the addition of the appropriate growth factor (GCT) and exposed to different concentrations of m-AMSA or Dx for 1 or 4 h, respectively. DNA-SSB were determined by alkaline elution techniques. Either the kinetics or the amounts of DNA-SSB caused by both topoisomerase II inhibitors were variable among different cases. By increasing m-AMSA concentrations there was a concomitant increase in DNA-SSB up to a plateau at the highest concentrations. Dx induced DNA-SSB followed a bell shape curve with a decrease in the number of breaks at the highest concentrations that was evident in most cases. The interindividual variability of Dx-induced DNA-SSB was not correlated with intracellular Dx concentrations as assessed by flow cytometry. No correlation was evident between the amount of DNA breaks induced by m-AMSA and that induced by Dx. These data suggest that AML cells derived from different patients are not necessarily cross-sensitive or cross-resistant to topoisomerase II inhibitors with different chemical structures such as amsacrine or anthracyclines.

Adult↗

PubMed1993

Combination of classical and interphase cytogenetics to investigate the biology of myeloid disorders: detection of masked monosomy 7 in AML.

Numerical abnormalities of chromosome 7 were detected by using fluorescence labeled in situ hybridization (FISH) procedure with a centromere-specific probe in four cases of acute myeloid leukemia (AML) and three cases of myelodysplastic syndromes (MDS). Comparison of these results with classical cytogenetic (CC) data demonstrated a good correlation between the two methods. FISH confirmed the finding of monosomy 7 in all patients who demonstrated this abnormality by CC. Two AML patients who did not show monosomy 7 by CC were unexpectedly found to contain this abnormality in 39.8% and 17% cells when examined by FISH. Given that our modified FISH method consistently yielded > 96% hybridization efficiency, these findings constitute an unexpected but real presence of monosomy 7 in a substantial number of interphase cells that had remained undetected by classical karyotyping. Finally, a number of maturing myeloid cells including granulocytes also demonstrated monosomy 7 by FISH, thereby confirming the ability of malignant cells to undergo differentiation. We conclude that FISH constitutes a highly sophisticated molecular technique which can be extremely useful in select cases for detecting 'masked monosomy 7' as well as helping to determine the lineage of terminally mature cells in AML, thereby providing a handle on the effects of cytokines or chemotherapy on normal vs leukemic clones.

Chromosomes, Human, Pair 7↗

PubMed1996

Cytogenetics and P-glycoprotein (PGP) are independent predictors of treatment outcome in acute myeloid leukemia (AML).

Clinical and biological features have recognized prognostic significance in acute myeloid leukemia (AML). To evaluate the interaction of these variables and weighted effect on treatment outcome, prognostic variables from 96 previously untreated patients were analyzed for association with expression of the MDR1 gene product P-glycoprotein (Pgp), and effect on response to induction chemotherapy, progression-free survival and overall survival. Multivariate relationships were analyzed using six prognostic variables, including age, cytogenetic pattern, gender, CD34+ surface phenotype, AML type (de novo versus secondary) and Pgp. Univariate comparisons indicate that Pgp (P = 0.0001), cytogenetic pattern (P = 0.0004) and a Cd34+ phenotype (P = 0.0005) are predictive of primary treatment failure, whereas Pgp (P = 0.0001) had the greatest predictive value in multivariate analysis. Only cytogenetic pattern retained prognostic significance (P = 0.0143) for response to induction therapy after adjustment for Pgp. Although all variable except gender were associated with Pgp, specimens harboring the favorable karyotypic abnormalities t(15;17), t(8;21) and inv(16) exclusively lacked Pgp expression. In a multivariate model, both Pgp and cytogenetic pattern predicted response and overall survival, whereas secondary AML and cytogenetic pattern influenced remission duration. These findings indicate that cytogenetic has prognostic relevance that is independent of Pgp, and implies the presence of undefined biological mechanisms affecting chemotherapy resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Severe polyethylene wear in total hip arthroplasty. Observations from retrieved AML PLUS hip implants with an ACS polyethylene liner.

A retrospective review was performed of 94 consecutive Anatomic Medullary Locking Plus (AML+, DePuy, Warsaw, IN) cementless acetabular components implanted between January 1988 and January 1990. All acetabular cups utilized the Acetabular Cup System (ACS) polyethylene liner (Depuy). Of these hips, 72 had been followed for more than 2 years (average, 43 months). There have been 15 (21%) clinical failures, all due to catastrophic wear of the acetabular polyethylene component surfaces. Of the 15 failures, clinical symptoms were absent in 7, an audible squeak was present in 3, and 5 patients reported having pain. All clinical failures had accelerated acetabular wear necessitating revision. Patients in the failure population were younger (56 years vs 62 years) than the remainder of the patients, and had greater cup abduction angles (55 degrees vs 49 degrees). All of the failed ACS polyethylene components had a 32 mm inner diameter articulating surface. The AML + acetabular component outer diameter averaged 56 mm (range, 50-64 mm). Six of 15 failures occurred in cups 58 mm or larger. Acetabular wear in the failure group was 0.77 mm/y (average). The incidence of acetabular (78%) and femoral (71%) osteolysis in the failure population is alarming. The rate of failure (21%) at 46 months of the AML + acetabular component with the ACS polyethylene liner appears to be related to design. The ACS design is flawed by a lack of hemispherical geometry, leading to failure at the superior rim with penetration of the femoral head through the polyethylene and against the metal shell.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗

PubMed2006

Are matched unrelated donor transplants justified for AML in CR1?

There has been controversy about the optimal consolidation therapy for patients with acute myeloid leukemia (AML) in first remission. Hematopoietic stem cell transplantation from human leukocyte antigen (HLA)-identical siblings has improved the survival of patients with unfavorable cytogenetics, but has not improved the survival of intermediate- or favorable-risk patients. If an HLA-identical sibling donor is not available, alternative sources of stem cells may be sought. HLA mismatched transplants are associated with an increased risk of graft rejection and graft-versus-host disease, and lower survival. Since large registries of HLA-typed volunteer donors have been established and the newer and more sensitive tissue typing technology can more clearly differentiate between matched and unmatched donors, some AML patients without an HLA-matched sibling have received transplants from an HLA-matched unrelated donor while in first remission. Data from the Center for International Blood and Marrow Transplant Research indicate that survival of patients with unfavorable cytogenetics appears at least as good with unrelated donor grafts as previously reported for matched sibling grafts, and better than consolidation chemotherapy. AML patients in first remission with unfavorable cytogenetics without a matched family donor should be offered an unrelated donor transplant.

Cytogenetics↗