Array-based DNA methylation profiling in acute myeloid leukaemia

Methylation in the promoter region of many genes is involved in regulating gene expression patterns. Using the Illumina GoldenGate^© methylation assay, we examined the methylation status of 1505 CpG‐sites from 807 genes in 32 samples from patients with acute myeloid leukaemia (AML) at diagnosis, nine at relapse and 15 normal controls and performed additional pyrosequencing and semiquantitative methylation specific polymerase chain reaction (MSP) of the GNMT promoter in 113 diagnostic AML samples. We found a gain of overall methylation in AML samples with a further increase at relapse. Regional hypermethylation as assessed by array analysis could be confirmed by both MSP and pyrosequencing. Additionally, large‐scale methylation analysis identified interesting candidate genes. Cluster analysis indicated that cytogenetic subgroups seemed to be characterized by additional distinct epigenetic modifications and that basic DNA methylation patterns remain at relapse. Therefore, promoter hypermethylation is a frequent event in AML and is accentuated at relapse. Array‐based methylation analysis determined distinct methylation profiles for non‐malignant controls and AML samples with specific chromosomal aberrations and can identify target genes for further evaluation.     

Childhood acute myeloid leukaemia

Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has demonstrated a complexity even greater than previously imagined. This complexity can be seen in the number and diversity of genetic alterations, epigenetic modifications, and characteristics of the leukaemic stem cells. The broad range of abnormalities across different AML subtypes suggests that improvements in clinical outcome will require the development of targeted therapies for each subtype of disease and the design of novel clinical trials to test these strategies. It is highly unlikely that further gains in long-term survival rates will be possible by mere intensification of conventional chemotherapy. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation.     

Characterization and prognostic significance of mitochondrial DNA variations in acute myeloid leukemia

Recent studies have suggested that mutations in the mitochondrial genome (mtDNA) may play a role in the development and response to treatment for human cancer. The aim of this study was to investigate whether mtDNA variations have any prognostic relevance, to clarify the spectra of mtDNA variation and to determine whether there was any correlation to known prognostic factors in acute myeloid leukemia (AML). To elucidate this, we sequenced the entire mtDNA in 56 AML patients and 14 control subjects. When analyzing the biologic impact of the non‐synonymous variations in the mtDNA coding genes, we found an inferior disease‐free survival for patients exhibiting variations in the two most important catalytic genes of the complex IV of the oxidative phosphorylation complexes (OXPHOS), that is, the cytochrome c oxidase subunit I and the cytochrome c oxidase subunit II (hazard ratio 2.6, P = 0.03; multivariate analysis). In addition, the most frequent variation was the T16311C in the control region, which was found in 11 (20%) of the 56 patients. This observation was confirmed in another cohort of 173 diagnostic AML samples. In this expanded group, the T16311C variation tended to be associated with chromosomal abnormalities.     

Mitochondrial cytochrome c oxidase subunit II variations predict adverse prognosis in cytogenetically normal acute myeloid leukaemia

Alterations in the two catalytic genes cytochrome c oxidase subunits I and II (COI and COII) have recently been suggested to have an adverse impact on prognosis in patients with acute myeloid leukaemia (AML). In order to explore this in further detail, we sequenced these two mitochondrial genes in diagnostic bone marrow or blood samples in 235 patients with AML. In 37 (16%) patients, a non‐synonymous variation in either COI or COII could be demonstrated. No patients harboured both COI and COII non‐synonymous variations. Twenty‐four (10%) patients had non‐synonymous variations in COI, whereas 13 (6%) patients had non‐synonymous variations in COII. The COI and COII are essential subunits of cytochrome c oxidase that is the terminal enzyme in the oxidative phosphorylation complexes. In terms of disease course, we observed that in patients with a normal cytogenetic analysis at disease presentation (CN‐AML) treated with curative intent, the presence of a non‐synonymous variation in the COII was an adverse prognostic marker for both overall survival and disease‐free survival (DFS) in both univariate (DFS; hazard ratio (HR) 4.4, P = 0.006) and multivariate analyses (DFS; HR 7.2, P = 0.001). This is the first demonstration of a mitochondrial aberration playing an adverse prognostic role in adult AML, and we argue that its role as a potentially novel adverse prognostic marker in the subset of CN‐AML should be explored further.     

Spontaneous remission in acute myeloid leukaemia

A summary of the literature of adult patients with acute myeloid leukaemia (AML) who have undergone spontaneous remission (SR) is presented together with a report of a patient whose SR was accompanied by cytogenetic remission. There are less than 20 reports of SR since the 1980s. SR is by no means synonymous with cure, since the average duration of the remission is only 7·1±9·2 months. Neither infections nor transfusions are absolute requirements of SR.     

Higher than normal mitochondrial DNA content associated with better outcome in acute promyelocytic leukaemia? Maybe

Mitochondrial biology may influence the outcome of therapy for acute promyelocytic leukemia if arsenic trioxide is not part of the treatment. Inclusion of arsenic trioxide in the treatment regimen may cancel the adverse impact of certain mitochondrial abnormalities frequently associated with the disease. Commentary on: Pereira-Martins et al. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia. Br J Haematol 2023;200:170-174.     

Antibody therapy for acute myeloid leukaemia

Novel therapies with increased efficacy and decreased toxicity are desperately needed for the treatment of acute myeloid leukaemia (AML). The anti CD33 immunoconjugate, gemtuzumab ozogamicin (GO), was withdrawn with concerns over induction mortality and lack of efficacy. However a number of recent trials suggest that, particularly in AML with favourable cytogenetics, GO may improve overall survival. This data and the development of alternative novel monoclonal antibodies (mAb) have renewed interest in the area. Leukaemic stem cells (LSC) are identified as the subset of AML blasts that reproduces the leukaemic phenotype upon transplantation into immunosuppressed mice. AML relapse may be caused by chemoresistant LSC and this has refocused interest on identifying and targeting antigens specific for LSC. Several mAb have been developed that target LSC effectively in xenogeneic models but only a few have begun clinical evaluation. Antibody engineering may improve the activity of potential new therapeutics for AML. The encouraging results seen with bispecific T cell‐engaging mAb‐based molecules against CD19 in the treatment of B‐cell acute lymphobalstic leukaemia, highlight the potential efficacy of engineered antibodies in the treatment of acute leukaemia. Potent engineered mAb, possibly targeting novel LSC antigens, offer hope for improving the current poor prognosis for AML.     

Adult acute myeloid leukaemia

The curability of acute myeloid leukaemia (AML) in a fraction of adult patients was demonstrated a long time ago. Currently, the probability of cure is consistently above fifty per cent in patients with de novo disease expressing favourable-risk associated cytogenetic features. Even better, the cure rate exceeds 75% in the acute promyelocytic subtype since the introduction of retinoic acid-containing regimens. In the meantime, continuing progress in supportive care systems and stem cell transplant procedures is making myeloablative therapies, when needed, somewhat less toxic—and thereby more effective—than in the recent past. Therefore, evidence is accumulating to indicate an improved therapeutic trend over the years, with the notable exception of older (>55 years) patients with adverse-risk chromosomal aberrations and/or leukemia secondary to myelodysplasia or prior cancer-related chemotherapy and/or radiotherapy. This review conveys the many facets of this progress, focusing on diagnostic subsets, risk classes, newer biological issues and conventional as well as innovative therapeutic interventions with or without autologous/allogeneic stem cell transplantation.     

Ultrastructural features in 100 cases of acute myeloid leukaemia

Ultrastructural features thought to be significant in acute myeloid leukaemia (AML) have been examined in 100 cases entered into the Medical Research Council 9th AML Trial. It is concluded that, of the features examined, only rarely is there a striking correlation with diagnosis which could be usefully employed with confidence. This is a consequence of there being both a large overlap of similar ultrastructural features between the different sub-types of the disease and also wide variations in ultrastructure within the conventionally diagnosed sub-types of AML. Thus the similarities between cells from different cases which allow them to be classified by light microscopy do not necessarily extend to the ultrastructural level. However, it is suggested that a classification on ultrastructural grounds might have a prognostic significance which would only be revealed by a long-term study.     

Isolated gingival relapse in acute myeloid leukaemia

A 47-yr-old man with acute myeloid leukaemia had been in complete remission for 18 months when he developed a gingival tumour. Histological examination revealed leukaemic infiltrate and, at this stage, no other signs of relapse could be demonstrated. Chemotherapy and local radiotherapy resulted in the disappearance of the mass; however, histological abnormalities persisted. First relapse of acute myeloid leukaemia presenting as a gingival tumour has not been previously reported.     

Clinical significance of serum thymidine kinase in adult T-cell leukaemia and acute myeloid leukaemia

To clarify the clinical and biological significance of serum thymidine kinase (TK) in adult T-cell leukaemia (ATL) associated with human lymphotropic virus type-I (HTLV-I) and in acute myeloid leukaemia (AML), TK was measured in 52 patients with ATL (acute ATL, 35 patients; lymphoma ATL, two patients; chronic ATL, 12 patients; smouldering ATL, three patients), and in 27 patients with AML (one FAB MO, one Ml, 10 M2, seven M3, five M4, one M5, one M6, one MU). In ATL patients, statistical analysis disclosed a close correlation between TK level and the leucocyte count (P<0–01), and absolute number of abnormal lymphocytes (P<0–01). However, no correlation was observed between serum lactic dehydrogenase (LDH) level and these items. Concerning the therapeutic response, a statistical difference was present in TK between complete remission and no response (P<005), but not in LDH. We also investigated a significant inverse correlation between TK level as well as LDH level and the length of survival after the initial diagnosis (P<001). In AML patients a close correlation of TK level with the count of leucocytes (P<001), percentage of blasts in the blood (P<005), therapeutic response (P<0–01) and the length of survival after the initial diagnosis (P< 005) was present.     

Epigenetics of paediatric acute myeloid leukaemia

Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently linked to treatment resistance and poor patient outcome. In this review, we discuss how the epigenetic mechanisms that underpin normal haematopoiesis are subverted in AML, and in particular how these processes are altered in childhood and adolescent leukaemias. We also provide a brief summary of the burgeoning field of epigenetic-based therapies, and how AML treatment might be improved through provision of better conceptual frameworks for understanding the pleiotropic molecular effects of epigenetic disruption.     

Necrotising dermatitis in refractory acute myeloid leukaemia

Severe cutaneous infections in leukaemic patients are difficult to treat and can rapidly become fatal. We report on a case of essential thrombocythemia evolved to a myelodysplastic syndrome and finally, to an overt myeloid leukaemia, refractory to chemotherapy. In the presence of a marked neutropenia, the patients developed a wide Staphylococcus epidermidis necrotising dermatitis. The diagnosis was made possible only by a skin biopsy culture and the antibiotic treatment, based on antimicrobial susceptibility tests, rapidly resolved the infection. In neutropenic patients, appropriate laboratory tests and treatment, can lead to recovery of life-threatening infections.