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PubMed1995

The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation.

The AML-1/CBF beta transcription factor complex is targeted by both the t(8;21) and the inv(16) chromosomal alterations, which are frequently observed in acute myelogenous leukemia. AML-1 is a site-specific DNA-binding protein that recognizes the enhancer core motif TGTGGT. The t(8;21) translocation fuses the first 177 amino acids of AML-1 to MTG8 (also known as ETO), generating a chimeric protein that retains the DNA-binding domain of AML-1. Analysis of endogenous AML-1 DNA-binding complexes suggested the presence of at least two AML-1 isoforms. Accordingly, we screened a human B-cell cDNA library and isolated a larger, potentially alternatively spliced, form of AML1, termed AML1B. AML-1B is a protein of 53 kDa that binds to a consensus AML-1-binding site and complexes with CBF beta. Subcellular fractionation experiments demonstrated that both AML-1 and AML-1/ETO are efficiently extracted from the nucleus under ionic conditions but that AML-1B is localized to a salt-resistant nuclear compartment. Analysis of the transcriptional activities of AML-1, AML-1B, and AML-1/ETO demonstrated that only AML-1B activates transcription from the T-cell receptor beta enhancer. Mixing experiments indicated that AML-1/ETO can efficiently block AML-1B-dependent transcriptional activation, suggesting that the t(8;21) translocation creates a dominant interfering protein.

Alternative Splicing↗

PubMed1996

AML-2 is a potential target for transcriptional regulation by the t(8;21) and t(12;21) fusion proteins in acute leukemia.

AML-1B is targeted directly and indirectly in multiple chromosomal translocations in myeloid and B-cells. The AML-1/ETO and TEL/AML-1 fusion proteins, created by the t(8;21) and t(12;21) respectively, disrupt AML-1B-dependent transcription. Recently, two human members of the runt homology domain family of transcription factors have been identified, AML-2 and AML-3, which also regulate transcription through enhancer core motifs. If multiple factors regulate transcription through the same site, a dominant interfering protein may be required to promote leukemogenesis, rather than the inactivation of both AML1 alleles. To determine which AML family proteins are active in hematopoietic cells, we developed antisera specific to each family member for use in gel mobility shift assays. We have found that AML-1B is the major DNA binding activity in T-cell lines, while both AML-1B and AML-2 are expressed in myeloid and B-cell lines. AML-1B represents most of the active protein in the mouse thymus, whereas AML-1 and AML-2 are equally expressed in the mouse spleen. AML-3 is expressed at very low levels in a single myeloid cell line, 32D.3, and is the only core binding activity present in Buffalo rat liver cells. We demonstrate that AML-2-dependent transactivation mediated by enhancer core motifs is inhibited by the AML-1/ETO and TEL/AML-1 fusion proteins. This indicates that the t(8;21) and t(12;21) fusion proteins inhibit transcriptional activation by the AML-1 transcription factor family, and in so doing contributes to leukemogenesis.

Acute Disease↗

PubMed2002

Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients.

The French-American-British (FAB) classification and the new World Health Organization (WHO) classification distinguish acute monoblastic leukaemia (AML M5a) from acute monocytic leukaemia (AML M5b). Not much is known about the underlying genetic differences leading to these clearly different phenotypes. We analysed 58 patients with de novo AML M5a and 66 patients with de novo AML M5b in comparison with a whole group of 1603 de novo AML. An aberrant karyotype was found in 75.9% of AML M5a but in only 28.8% of M5b (P < 0.0001) and in 54.7% of all other AML subtypes (P = 0.0015). 11q23/MLL aberrations were detected in 31% of M5a, 12.1% of M5b (P = 0.01) but only 1.3% of all other AML subtypes (P < 0.0001). Trisomy 8 as the sole cytogenetic aberration was found in 22.4% of M5a, but in only 3% of M5b and in 2.5% of all other AML subcategories (P < 0.0001). Although the frequency of the MLL-partial tandem duplication (MLL-PTD) did not differ between the three cohorts (1.7%, 4.5% and 6.1% respectively, NS), the detection of FLT3 length mutations (FLT3-LM) differed significantly. AML M5a showed a low frequency of only 6.9%, but 28.8% of M5b (P = 0.0014) and 23.5% of all other AML revealed a FLT3-LM. In conclusion, we demonstrated genetic, i.e. biological, differences between AML M5a and AML M5b and all other AML. Therefore, AML M5 should further be categorized as two different groups, as proposed by the WHO classification.

Adolescent↗

PubMed1997

CD34+ megakaryoblastic leukaemic cells are CD38-, but CD61+ and glycophorin A+: improved criteria for diagnosis of AML-M7?

The aim of this flow cytometry study in acute megakaryoblastic leukaemia (AML-M7) was to describe the membrane phenotype of CD34+ progenitor subsets and compare these with the phenotypes expressed by other AML FAB types. Following conventional histopathological diagnosis mononuclear cells from bone marrow and blood were examined in seven patients with AML-M7 and compared with results from 26 sequential patients with AML-M0 to AML-M6. The CD34+ subsets in AML-M7 patients differed from that of patients with AML-M0 to AML-M6 as the CD34+ CD61+ and the CD34+ Glycophorin A+ subsets were median 31% and 20%, respectively, compared to 4% and 2% in the AML-M0 to AML-M6 (P = 0.0005). Only 1% of the CD34+ progenitors were CD34+ CD38+ in AML-M7 compared to 72% in other AML subtypes (P < 0.000). These findings suggest that the CD34+ cell compartment in AML-M7 consists of early lineage-specific progenitors. In conclusion, flow cytometry analysis of CD34+ subsets may improve the diagnostic safety in AML-M7 and consequently the prognostic significance of immunophenotyping in acute leukaemia.

Adult↗

PubMed1999

Modulatory in vitro effects of interleukin-1 receptor antagonist (IL-1Ra) or antisense oligonucleotide to interleukin-1 beta converting enzyme (ICE) on acute myeloid leukaemia (AML) cell growth.

We investigated the effects of interleukin-1 receptor antagonist (IL-1Ra) on the spontaneous proliferation and AML colony forming unit (CFU-AML) formation of bone marrow and peripheral blood cells in 50 acute myeloid leukaemia (AML) patients. Exposure to IL-1Ra (10 micrograms/ml) caused either decreased, unaltered or increased AML cell proliferation, as well as of CFU-AML colony formation, depending on the individual patient, but the inhibitory effects were dominant. To evaluate the involvement of IL-1 beta converting enzyme (ICE) in the autonomous AML cell growth, the effects of an antisense oligonucleotide on ICE were examined in 19 of these patients. In a majority of patients, antisense ICE suppressed both AML cell proliferation and CFU-AML although a stimulatory effect was sometimes evident. The proportion of AML patients with suppression obtained by antisense ICE was higher than with IL-1Ra, suggesting the involvement of additional ICE-dependent cytokine(s) in AML cell growth besides IL-1. The presence of IL-1Ra or antisense ICE also suppressed the endogenous IL-1 beta production of AML cells, at both the level of pro-IL-1 beta and mature IL-1 beta. Although inhibition by IL-1Ra or antisense ICE on growth parameters of AML cells in vitro prevailed, indicating the importance of IL-1 activity in autonomous AML cell growth, stimulatory effects on the cells of some patients suggest that AML is a heterogenous disorder regarding IL-1 beta regulation.

Acute Disease↗

PubMed1993

[Clinical significance of micromegakaryocytes in de novo AML].

Bone marrow specimens obtained from 54 patients with de novo AML and 7 patients with AML evolving from MDS were retrospectively examined for the presence of micromegakaryocytes defined as cells of less than 30 microns in diameter with one or two nuclei. At least 25 megakaryocytes were counted in each patient. Micromegakaryocytes were found in 17 cases (31%), M1:1/11, M2:5/18, M3:0/4, M4:5/12, M5:1/4, M6:4/4, M7:1/1. The median age of the patients was higher in de novo AML with micromegakaryocytes (57 years) than in de novo AML without micromegakaryocytes (41 years) (p = 0.014). Chromosomal analysis revealed that deletion of 5 or 5q-, 7 or 7q- was recognized only in the group of de novo AML with micromegakaryocytes and that t(15;17), t(8:21) and inv (16) were not recognized in this group. Micromegakaryocytes were identified in each bone marrow specimen obtained from 9 of 10 patients with de novo AML with trilineage myelodysplasia. The complete remission rate was significantly lower in de novo AML with micromegakaryocytes (33%) than in de novo AML without micromegakaryocytes (86%) (p = 0.001). The duration of survival of the patients with de novo AML with micromegakaryocytes was shown to be shorter than that of the patients with de novo AML without micromegakaryocytes (p = 0.017). Micromegakaryocytes were recognized in all of 7 patients with AML evolving from MDS. The presence of micromegakaryocytes in bone marrow of the patients with AML indicates a subset of AML with poor prognosis that may be closely associated with myelodysplastic syndrome.

Adolescent↗

PubMed1996

Regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors in a GM-CSF-dependent human myeloid leukemia cell line (AML-193) by interleukin-6.

AML-193 is a cytokine-dependent human leukemia cell line established from the bone marrow of an M5-type acute monocytic leukemia (AML) patient. The effect of recombinant human interleukin-6 (rhIL-6) on the proliferation of AML-193 cells was investigated. Both granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and rhIL-3 promoted the DNA synthesis and growth of AML-193 cells in vitro. rhIL-6 alone did not support the growth of AML-193 cells, yet pretreatment of AML-193 cells with rhIL-6 markedly enhanced their proliferative response to subsequent rhGM-CSF or rhIL-3 stimulation. The growth-promoting effect induced by rhIL-6 was attributable in part to the upregulation of GM-CSF receptors on AML-193 cells; treatment of AML-193 cells with rhIL-6 for 24 to 48 hours greatly increased their GM-CSF binding activity, which occurred in a dose-dependent manner. Both the growth-promoting and receptor-upregulating effects induced by rhIL-6 could be blocked by treating AML-193 cells with neutralizing anti-gp130 antibodies (GPX7). Treatment of AML-193 cells with anti-gp130 antibodies alone also led to a notable decline in GM-CSF binding activity, suggesting a possible role of gpl30 in regulating the expression of GM-CSF receptors. When AML-193 cells were starved in cytokine-free medium and then restimulated with rhGM-CSF, a rapid increase (5 minutes) in lyn kinase activity was observed. A similar upregulation of lyn kinase activity by rhIL-6 treatment also was noted in AML-193 cells, but only after a prolonged incubation of the cells with rhIL-6 (>24 hours). These findings show that the growth-promoting effects of rhIL-6 are mediated through the upregulation of GM-CSF receptors on AML-193 cells by mechanisms that appear to involve the activation of both gp130 and lyn kinase.

Antigens, CD↗

PubMed1997

Minimally differentiated acute myeloid leukemia (AML-M0): comparison of 25 cases with other French-American-British subtypes.

We compared the immunophenotypic and karyotypic features of 25 cases of minimally differentiated acute myeloid leukemia (AML-M0) with those of 247 cases comprising all AML French-American-British (FAB) classification. Myeloperoxidase (MPO) was detectable with a specific monoclonal antibody in all cases of AML-M0, whereas CD13 and CD33 were both negative in 4 of the 25 cases. Thus, anti-MPO reliably detects minimal myeloid differentiation in AML-M0. CD34 and terminal deoxynucleotidyl transferase (TdT) were more frequently expressed in AML-M0 (96% and 68% of the cases, respectively) than in the other FAB subsets (P < .001 for both). By contrast, GP-170 and CD7 were less frequently expressed in AML-M0 than in FAB classes such as M1, M4, and M5 (P = .02 and .003, respectively). A total of 80% of AML-M0 cases carried lymphoid markers (including TdT), and 48% showed a coordinate positivity for two or more of them. CD2, CD5, CD10, and CD19 were expressed in a similar fashion among the different FAB groups, whereas CD4 expression was significantly more frequent in AML-M0, AML-M4, and AML-M5 (P = .014). AML-M0 was characterized by a more frequent occurrence of complex karyotypes. In addition, approximately 20% of cases had TdT positivity, complex karyotypes, and anomalies of chromosome 5 and/or 7, a pattern not observed in the other FAB subsets. Finally, 80% of anomalies of chromosome 5 and/or 7 in AML-M0 were comprised within complex karyotypes, whereas only 13% of the remaining FAB cases carried this feature. In summary, AML-M0 frequently expresses immunophenotypic and karyotypic aspects that are likely to identify a "stem cell" pattern.

Adolescent↗

PubMed2003

Prognostic value of AML 1/ETO fusion transcripts in patients with acute myelogenous leukemia.

BACKGROUND: The t (8;21) (q22;q22), which produces the fusion gene AML1/ETO, is associated with relatively good prognosis and, in particular, with a good response to cytosine arabinoside. Analysis of t (8;21) positive leukemic blasts has shown characteristic morphological and immunological features. We performed this study to investigate the incidence of AML1/ETO rearrangement in adult acute myelogenous leukemia (AML), especially in M2 subtype, to make a comparison of clinical, morphological and immunophenotypic characteristics between AML1/ETO rearrangement positive and negative group in patients with AML and to analyze the correlation with other biological parameters. METHODS: From May 1995 to Sept. 2000, fifty-nine patients with AML, including twenty-nine AML-M2, were studied. RNAs were extracted from leukemic cells and reverse transcriptase mediated polymerase chain reaction (RT-PCR) for AML1/ETO fusion transcript was done. Chromosome study, immunophenotypic and clinical characteristics were analyzed and statistical analysis was done. RESULTS: The incidence of AML1/ETO fusion transcripts was 22.0% in AML and 44.8% in AML-M2. The morphologic finding of bone marrow in AML-M2 showed higher incidence of Auer rods, large blast with prominent golgi and abnormal granules in AML1/ETO positive patients. There was no significant difference of immunophenotype. AML patients with AML1/ETO had a tendency of higher complete remission rate (81.8% vs 56.6%, p = 0.13). The overall survival (median; 82.2 weeks vs 34.4 weeks, p = 0.02) and progression free survival (median; 50.9 weeks vs 20.4 weeks, p = 0.02) of AML1/ETO positive group were longer than those of the negative group in AML. AML-M2 patients with AML1/ETO rearrangement had also a tendency of longer overall survival and progression free survival, although there was no significant difference between both groups. CONCLUSION: Our data suggest that AML1/ETO rearrangement is detected frequently in AML, especially M2, and is a favorable prognostic factor. Thus, molecular diagnostic approaches should be used routinely to identify patients with this gentic subtype of AML.

Adolescent↗

PubMed2007

Improved outcome in childhood acute myeloid leukemia in Singapore with the MRC AML 10 protocol.

BACKGROUND: The introduction of the United Kingdom Medical Research Council's 10th AML trial (MRC AML 10) protocol incorporating high-dose anthracycline therapy has improved outcome of children with acute myeloid leukemia (AML). In this study, we review the results of childhood AML therapy in a Singapore university hospital over the last 17 years emphasizing toxicity and outcome. PROCEDURE: Retrospective analysis revealed 34 children with AML between 1988 and 2003. Prior to September 1996, therapy consisted of: POG-8498 (n = 10), others (n = 9). From September 1996, all but one of 15 children received MRC AML 10 treatment. RESULTS: At the time of analysis, 17 had died from disease, and 17 patients were alive among whom 2 had relapsed. MRC AML 10-treated patients (n = 14) had significantly better 3-year overall, event-free, and disease-free survival (74% vs. 35%, 77% vs. 20%, 83% vs. 31%; P = 0.019, P = 0.002, and P = 0.010, respectively) and were likelier to achieve complete remission (CR) than non-MRC AML 10 patients (P = 0.102). Among patients who achieved CR, MRC AML 10-treated patients were significantly more likely to achieve CR after only one cycle of chemotherapy (P = 0.016). Hematologic toxicity was similar among the different regimens (P = 0.9). CONCLUSIONS: These findings suggest that MRC AML 10 treatment results in significantly superior survival, without excess toxicity. Future studies should attempt to elucidate the relative importance of individual MRC AML 10 components and reduce the high cumulative anthracycline dose without compromising outcome.

Acute Disease↗

PubMed2007

Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML.

BACKGROUND: Anthracyclines are effective antineoplastic drugs in acute myelogenous leukemia (AML). However, their use is limited by cardiomyopathy, which occurs in children already at cumulative doses of 300 mg/m(2) (given as daunorubicin equivalent). PROCEDURE: To evaluate anthracycline-associated cardiomyopathy in pediatric AML-patients, the incidence of early and late (>1 year after intensive AML chemotherapy) clinical and subclinical cardiotoxicity was analyzed out of a total of 1,207 patients <18 years treated between 1993 and 2003 in trials AML-BFM93/98: 1,010 protocol patients with de novo AML, 121 with Down syndrome (DS)-AML, and 76 with secondary AML. The cumulative dose of anthracyclines was generally risk-adapted: 300-450 mg/m(2) using 1-4-hr infusions of anthracyclines with the assumed lowest cardiotoxic potential. Eight hundred eighty-five patients (73%) were eligible for the analysis of early and 547 (45%) of late cardiotoxicity (1,399 follow-up data). RESULTS: Thirty-eight patients (4.3%), including 3 DS-AML and 1 secondary AML, suffered from early cardiomyopathy. After 5 years, four patients showed temporarily or persistently a reduced shortening fraction, which led to death in one DS-AML patient. Including these 4 patients, late cardiomyopathy was seen in 16 patients (cumulative incidence after 11 years: 5% +/- 1%). Nine patients (2.5 +/- 1%) showed clinical symptoms, five of them had persistent abnormal shortening fraction. Late subclinical cardiomyopathy occurred temporarily in seven patients. Late clinical cardiomyopathy mainly affected patients with a second anthracycline therapy (secondary malignancy) and those with early cardiotoxicity. CONCLUSION: In spite of a highly intensive and effective treatment, the frequency of anthracycline-associated cardiomyopathy was low in the AML-BFM studies.

Acute Disease↗

PubMed2004

High expression of costimulatory molecules correlates with low relapse-free survival probability in acute myeloid leukemia (AML).

Costimulatory molecules such as lymphocyte function-associated antigen (LFA)-1 (CD11a), LFA-3 (CD58), intercellular adhesion molecule (ICAM)-1 (CD54), neuronal cell adhesion molecule (NCAM) (CD56), B7-1 (CD80), or B7-2 (CD86) are important regulatory elements in healthy immunological cascades, but their role in acute myeloid leukemia (AML) has only been rarely investigated. We studied their expression on mononuclear bone marrow (BM) cells from 105 patients with AML at initial diagnosis and evaluated their prognostic significance. Fluorescence-activated cell sorter (FACS) analyses were performed using antibodies directly conjugated with fluorescein. A BM sample was considered positive if more than 20% of the cells in the blast containing gate expressed the respective marker. The surface expression of CD11a (27 of 29 cases positive with an average of 71% positive blasts; 27(+)/29, 71%), CD54 (23(+)/33, 37%), CD56 (24(+)/93, 20%), CD58 (29(+)/29, 95%), CD80 (13(+)/28, 30%), and CD86 (19(+)/29, 39%) was measured. The expression of these markers in different French-American-British (FAB) classification types (M0-M5) was heterogeneous, except for CD56, which showed a higher proportion of positive cells in monocytic subtypes of AML. In addition, cases with a "poor risk" karyotype as well as patients succumbing to "early death" after double induction therapy according to the AML Cooperative Group (CG) protocol were characterized by a high expression of CD56. Relapse-free survival analyses demonstrated that patients with more than 8% CD56(+) cells in the BM relapsed significantly sooner. CD54 was preferentially expressed in AML M4(eo) and in addition in "favorable" cytogenetic risk groups and in cases that had responded to AML-CG therapy. Only very high proportions (>60%) of CD54(+) cells were associated with a lower probability for relapse-free survival. CD80 and CD86 expressions were similar in all FAB types. Patients who had responded to AML-CG therapy showed higher CD80 proportions and lower CD86 proportions compared to the "nonresponder" group. Whereas cases with more than 15% CD80(+) cells had a significantly lower probability for relapse-free survival, only cases with more than 65% CD86(+) were characterized by a significantly lower probability for relapse-free survival. Expression profiles of CD11a and CD58 were not associated with specific FAB types or prognostically relevant groups. We can conclude: (1) Expression of costimulatory molecules in AML is very variable. This reflects the great diversity of immunophenotypes in AML. (2) CD56 is mainly expressed in monocytic subtypes of AML. CD56(+) subtypes of AML seem to be a separate entity with a worse prognosis independent of the karyotype. (3) High expression of some costimulatory molecules correlates with a worse prognosis concerning relapse-free survival times.

Antigens, CD↗

PubMed2002

Expression of endothelial cell-associated molecules in AML cells.

Recently, it has been clarified that interaction between hematopoietic cells and endothelial cells is important in normal hematopoiesis and leukemogenesis. In this study, we examined the relationship between AML cells and endothelial cells by analyzing the expression profile of angiogenic factors, angiopoietin-1 (Ang-1), Ang-2, Tie-2 (a receptor for angiopoietins) and vascular endothelial growth factor (VEGF). Our results demonstrated that CD7(+)AML expressed Ang-2 mRNA frequently and integrin-family adhesion molecules (CD11c and CD18) intensively, suggesting the close correlation with endothelial cells. On the other hand, in t(8;21) AML cells, expression of Ang-2 was infrequent and expression of integrin-family adhesion molecules (CD11b, CD11c and CD18) was weak, suggesting the sparse association with endothelial cells. As for CD7(+)AML cells, despite the frequent and intense expression of endothelial cell-associated molecules (such as Ang-2, CD11c and CD18), intensity of Tie-2 expression was quite low (P < 0.05). Ang-2 expressed in CD7(+)AML cells is not considered to act in an autocrine fashion, but to work on endothelial cells to "feed" leukemic cells. Although Ang-2 is recognized as a natural antagonist for Tie-2, our data presented here suggested the alternative role of Ang-2 in the relationship between endothelial cells and leukemia cells, at least in a subset of leukemia such as CD7(+)AML. These results were supported by the study using AML cell lines, KG-1 (CD7 negative) and its subline KG-1a (CD7 positive); KG-1 had mRNA expression profile of Ang-1(+)Ang-2(-)Tie-2(+), while KG-1a showed Ang-1(+)Ang-2(+)Tie-2(-). These difference in the expression profile of angiogenic factors between CD7(+)AML and t(8;21)AML may explain the characteristic morphological features of these leukemias (CD7(+)AML as blastic type and t(8;21)AML as differentiative type).

Acute Disease↗

PubMed2003

Low expression of the myeloid differentiation antigen CD65s, a feature of poorly differentiated AML in older adults: study of 711 patients enrolled in ECOG trials.

CD65s appears when the progenitor antigen CD34 disappears, suggesting that this sialylated carbohydrate antigen marks a turning point in normal myeloid differentiation. We characterized acute myeloid leukemia (AML) with low CD65s expression (CD65s(low) AML) in 711 patients entered on seven Eastern Cooperative Oncology Group AML treatment trials (1986-1999). Of those, 198 (28%) qualified as having CD65s(low) AML. Morphologically, CD65s(low) AML was more common in FAB subgroups with minimal differentiation, M0/M1 (P=<0.0001). Early precursor antigens CD34, CD117 and terminal transferase were more frequent in CD65s(low) than CD65s(high) AML (P=<0.0001). Myeloperoxidase was present in fewer CD65s(low) myeloblasts, and the more mature myeloid antigens, CD15 and CD11b, were rarely detected (P=<0.0001). Yet, the two diagnoses did not differ in the distribution of cytogenetic prognostic groups or the occurrence of the multidrug-resistance mediator, P-glycoprotein. CD65s(low) AML patients were significantly older than CD65s(high) cases (P<0.0001). Furthermore, the incidence of CD65s(low) cases increased with age, from 20% in patients under the age of 50 years to 67% in patients older than 80 years (P<0.0001). Overall, complete remission (CR) rate and overall survival were comparable in CD65s(low) and CD65s(high) AML. However, among patients >55 years of age, CD65s(low) AML had a decreased CR rate of 33 vs 44% in CD65s(high) AML (P=0.055). Thus, CD65s(low) AML represents immunophenotypically undifferentiated disease and occurs predominantly in older adults. Although not statistically significant, the observed association between low CD65s expression and decreased CR rate only in patients over the age of 55 is intriguing.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials.

Between 1988 and 2002, 758 children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12. MRC AML 10 tested the role of bone marrow transplantation following four blocks of intensive chemotherapy and found that while both allogeneic bone marrow transplant (allo-BMT) and autologous bone marrow transplant (A-BMT) significantly reduced the relapse risk (RR), this did not translate into a significant improvement in overall survival (OS). A risk group stratification based on cytogenetics and response to the first course of chemotherapy derived from MRC AML 10 was used to deliver risk-directed therapy in MRC AML 12. Allo-BMT was limited to standard and poor risk patients and A-BMT was not employed. Instead, the benefit of an additional block of treatment was tested by randomising children to receive either four or five blocks of treatment in total. While the results of MRC AML 12 remain immature, there appears to be no survival advantage for a fifth course of treatment. The 5 year OS, disease-free survival (DFS), event-free survival (EFS) and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5-year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. MRC AML trials employ a short course of triple intrathecal chemotherapy alone for CNS-directed treatment and CNS relapse is uncommon. Improvements in supportive care have contributed to improved outcomes and the number of deaths in remission fell between trials. Anthracycline-related cardiotoxicity remains a concern and the current MRC AML 15 trial tests the feasibility of reducing anthracycline dosage without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose ara-C. MRC studies suggest that the role of allo-BMT is limited in 1st CR and that there may be a ceiling of benefit from current or conventional chemotherapy.

Acute Disease↗

PubMed2007

Expression of the target receptor CD33 in CD34+/CD38-/CD123+ AML stem cells.

BACKGROUND: CD33 (Siglec-3) is becoming increasingly important as a target of antibody-mediated therapy in acute myeloid leukaemia (AML). In normal myelopoiesis, expression of CD33 is restricted to advanced stages of differentiation, whereas primitive stem cells do not express CD33. In the present study, we asked whether leukaemic stem cells in patients with AML express CD33. MATERIALS AND METHODS: A multicolour-staining technique was applied in 11 patients with AML, and leukaemic progenitors defined as CD34(+)/CD38(-)/CD123(+) cells. AML stem cells were purified by cell sorting and were examined for expression of CD33 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: In all patients in whom the majority of myeloblasts expressed CD33 (n = 8), AML progenitors reacted with the CD33 antibody P67.6. Repopulation experiments utilizing irradiated NOD/SCID mice confirmed that AML stem cells in these patients reside within the CD33(+) subpopulation of the leukaemic clone. Moreover, highly purified AML stem cells (> 98% purity) from patients with CD33(+) AML were found to express CD33 mRNA in RT-PCR analyses. CD33 was neither detectable on CD34(+)/CD38(-) cells in normal bone marrow nor on leukaemic stem cells in patients with CD33-negative AML. CONCLUSIONS: Leukaemic stem cells in patients with CD33(+) AML express CD33. This observation is in favour of novel treatment concepts employing CD33-targeting antibodies in AML.

Acute Disease↗

PubMed2000

Lymphokine-activated killer (LAK) cells and cytokines synergize to kill clonal cells in acute myeloid leukemia (AML) in vitro.

We studied the influence of autologous lymphokine-activated-killer (LAK) cells on the survival of clonal and CD34-positive bone marrow (BM) cells from patients with acute myeloid leukemia (AML) in a coculture assay in vitro. (1) LAK cells were grown in the presence of IL-2, in some cases additionally with IL-6. (2) These cytotoxic cells were cocultured with (untreated or cytokine pretreated) AML-BM cells obtained at different stages of the disease. Therefore BM cells were (a) either frozen in liquid nitrogen or (b) precultured for 14 days with cytokines: IL-1beta, IL-3, IL-6, erythropoietin (EPO), stem cell factor (SCF) with ('Cytok1') or without granulocyte macrophage colony stimulating factor (GM-CSF) ('Cytok2') or with no added cytokines ('ISC/FCS') as a control. (3) Southern blot analysis was used to detect clonal BM cells. At diagnosis, 76 of 151 cases (50%) studied showed clonal gene rearrangements in marker genes. (4) Southern blot analysis and flow cytometry were used to compare the amount of clonal and CD34 positive BM cells before and after coculture procedures. Coculture experiments with untreated BM and autologous LAK cells led to a reduction of clonal cells in 2 of 5 cases at diagnosis, in 11 of 17 BM samples in complete remission but not in the one case studied at relapse. Similar results were found if precultured AML cells (with or without cytokines) were cocultivated with LAK cells. However the cytotoxic effect of LAK cells was more pronounced if cytokines (especially GM-CSF and SCF) were comprised. Our data indicate, that (1) clonality in AML can be demonstrated by Southern blot analysis; (2) CD34 positive cells in AML are clonal, gene rearranged cells; (3) clonal cell populations persist in BM during complete remission and relapse in most of the patients; (4) incubation of AML-BM cells with LAK cells lead to a reduction of clonal, rearranged cells in 11 of 17 AML cases in complete remission, but only in 2 of 6 cases at diagnosis or relapse; (5) AML cells can be sensitized to theLAK cell treatment by preincubation of AML-BM cells with cytokines (IL-1beta, IL-3, IL-6, SCF, EPO and GM-CSF) or by adding SCF to the coculture conditions. Southern blot analysis and flow cytometry are appropriate methods to detect and quantify leukemic disease. Cytokines and LAK cells synergize to kill AML blasts in vitro. This is a feasible approach to immunotherapy of AML and merits further investigations.

Acute Disease↗

PubMed2006

Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961.

To assess the impact of minimally differentiated acute myeloid leukemia (AML-M0) morphology in children, we analyzed 2 sequential Children's Cancer Group AML clinical trials. We compared presenting characteristics and outcomes of 82 CCG-2891 and CCG-2961 patients with de novo, non-Down syndrome (DS) AML-M0 with those of 1620 patients with non-M0 AML, and of 10 CCG-2891 patients with DS-associated AML-M0 with those of 179 with DS-associated non-M0 AML. Morphology and cytogenetics were centrally reviewed. The non-DS AML-M0 children had a lower white blood cell (WBC) count (P = .001) than their non-M0 counterparts and a higher incidence of chromosome 5 deletions (P = .002), nonconstitutional trisomy 21 (P = .027), and hypodiploidy (P = .002). Outcome analyses considering all children with non-DS AML demonstrated no significant differences between M0 and non-M0 patients. Analyses restricted to intensive-timing CCG-2891 and CCG-2961 demonstrated comparable complete response (CR) rates (79% and 78%) between non-DS M0 and non-M0 patients. Overall survival (OS) from diagnosis (38% +/- 14% versus 51% +/- 3%; P = .160) was not significantly different between the 2 groups. OS from end of induction (45% +/- 17% versus 63% +/- 3%; P = .038), event-free survival (EFS; 23% +/- 11% versus 41% +/- 3%; P = .018), and disease-free survival (DFS; 31% +/- 14% versus 52% +/- 3%; P = .009) were inferior in the M0 group. There was no significant outcome difference between DS-associated AML-M0 and non-M0 children. This study suggests that intensively treated non-DS-associated AML-M0 children have an inferior outcome compared with children with non-M0 AML.

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