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Nature Reviews. Clinical Oncology May 2016Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities... (Review)
Review
Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine.
Topics: Acute Disease; Drug Therapy; Genetic Predisposition to Disease; Humans; Leukemia, Myeloid; Models, Genetic; Molecular Targeted Therapy; Mutation; Nucleophosmin; Prognosis; Risk Factors
PubMed: 26620272
DOI: 10.1038/nrclinonc.2015.210 -
The FEBS Journal Aug 2022It is essential to relate the biology of acute leukaemia to normal blood cell development. In this review, we discuss how modern models of haematopoiesis might inform... (Review)
Review
It is essential to relate the biology of acute leukaemia to normal blood cell development. In this review, we discuss how modern models of haematopoiesis might inform approaches to diagnosis and management of immature leukaemias, with a specific focus on T-lymphoid and myeloid cases. In particular, we consider whether next-generation analytical tools could provide new perspectives that could improve our understanding of immature blood cancer biology.
Topics: Acute Disease; Hematopoiesis; Humans; Leukemia, Myeloid, Acute
PubMed: 34028982
DOI: 10.1111/febs.16030 -
Current Opinion in Hematology Jul 2014This review highlights recent insights into the roles of microRNAs (miRNAs) in pathogenesis of myeloid malignancies and tantalising prospects of miRNA therapy. (Review)
Review
PURPOSE OF REVIEW
This review highlights recent insights into the roles of microRNAs (miRNAs) in pathogenesis of myeloid malignancies and tantalising prospects of miRNA therapy.
RECENT FINDINGS
New roles for miRNAs in biological and disease processes are constantly being discovered. Although great effort has been put into identifying and cataloguing aberrantly expressed miRNAs in leukaemia, very little is known about the functional consequences of their deregulation in myeloid malignancies. This review will discuss the significance of powerful oncogenic miRNAs such as miR-22 in self-renewal and transformation of haematopoietic stem cells, as well as their ability to induce epigenetic alterations in the pathogenesis of the stem cell disorder myelodysplastic syndromes and myeloid leukaemia.
SUMMARY
Improved understanding of biological roles of miRNAs in the pathogenesis of haematological malignancies will allow rational stratification of patients and provide new therapeutic entries for the treatment of myelodysplastic syndromes and leukaemia.
Topics: Animals; Cell Transformation, Neoplastic; Humans; Leukemia, Myeloid; MicroRNAs; Molecular Targeted Therapy; Myelodysplastic Syndromes
PubMed: 24870972
DOI: 10.1097/MOH.0000000000000054 -
Annals of Medicine Dec 2022DNA methylation is considered an essential epigenetic event during leukaemogenesis and the emergence of drug resistance, which is primarily regulated by DNA... (Review)
Review
DNA methylation is considered an essential epigenetic event during leukaemogenesis and the emergence of drug resistance, which is primarily regulated by DNA methyltransferases. DNA methyltransferase-1 (DNMT1) is one of the members of DNA methyltransferases, in charge of maintaining established methylation. Recently, DNMT1 is shown to promote malignant events of cancers through the epigenetic and non-epigenetic processes. Increasing studies in solid tumours have identified DNMT1 as a therapeutic target and a regulator of therapy resistance; however, it is unclear whether DNMT1 is a critical regulator in acute myeloid leukaemia (AML) and how it works. In this review, we summarized the recent understanding of DNMT1 in normal haematopoiesis and AML and discussed the possible functions of DNMT1 in promoting the development of AML and predicting the sensitivity of hypomethylation agents to better understand the relationship between DNMT1 and AML and to look for new hope to treat AML patients.Key messagesThe function of DNA methyltransferase-1 in acute myeloid leukaemia.DNA methyltransferase-1 predicts the sensitivity of drug and involves the emergence of drug resistance.
Topics: DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Humans; Leukemia, Myeloid, Acute
PubMed: 35838271
DOI: 10.1080/07853890.2022.2099578 -
British Journal of Haematology Feb 2014Novel therapies with increased efficacy and decreased toxicity are desperately needed for the treatment of acute myeloid leukaemia (AML). The anti CD33 immunoconjugate,... (Review)
Review
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.
Topics: Animals; Antibodies, Monoclonal; Humans; Leukemia, Myeloid, Acute
PubMed: 24321020
DOI: 10.1111/bjh.12691 -
British Journal of Haematology Jan 2020The recognition of the curative potential of the graft-versus-leukaemia effect for patients with acute myeloid leukaemia (AML) undergoing stem cell transplantation, and... (Review)
Review
The recognition of the curative potential of the graft-versus-leukaemia effect for patients with acute myeloid leukaemia (AML) undergoing stem cell transplantation, and the emergence of immunotherapy as a powerful weapon to treat cancer, has spurred the exploration of the immune landscape of AML to apply immunotherapeutic approaches to curing the disease. While current concepts of cancer immunology and immunotherapy have relevance, there are also unique aspects of immune dysregulation in AML to be considered when designing rational immunotherapy for this leukaemia. This is timely because rapid advances in cancer immunobiology, together with technological developments have opened up the field of immunotherapy for malignant disease. Here the current knowledge of AML immunobiology is summarized together with a description of new immunotherapies to counter immunosuppression and immune evasion by AML. Recent advances in treatment with recombinant antibodies, adoptive cell therapy and vaccines and their future promise in AML treatment are reviewed.
Topics: Allografts; Antineoplastic Agents, Immunological; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Recombinant Proteins; Stem Cell Transplantation; Tumor Escape
PubMed: 31782805
DOI: 10.1111/bjh.16310 -
British Journal of Haematology Apr 2016Umbilical cord blood is a haematopoietic progenitor cell source for patients with acute myeloid leukaemia (AML), other haematological malignancies and metabolic diseases... (Review)
Review
Umbilical cord blood is a haematopoietic progenitor cell source for patients with acute myeloid leukaemia (AML), other haematological malignancies and metabolic diseases who can be cured by allogeneic haematopoietic cell transplantation, but who do not have a human leucocyte antigen compatible related or unrelated donor. Although the first cord blood transplants were done in children, there are currently more cord blood transplants performed in adults. In this review, we explore the history of umbilical cord blood transplantation, paediatric and adult outcome results, and novel trends to improve engraftment and reduce infection. Umbilical cord blood transplantation cures approximately 30-40% of adults and 60-70% of children with AML. Controversial issues, including the use of double versus single cord blood units for transplantation, optimal cord blood unit selection, infection prophylaxis, conditioning regimens and graft versus host disease prophylaxis, will be reviewed. Finally, comparison to other graft sources, cost, access to care, and the ideal graft source are discussed.
Topics: Adult; Allografts; Cord Blood Stem Cell Transplantation; Graft vs Host Disease; Humans; Infant; Leukemia, Myeloid, Acute; Unrelated Donors
PubMed: 26766286
DOI: 10.1111/bjh.13926 -
Clinical and Translational Medicine Jun 2023Genetic mutations of IKZF1 have been frequently delineated in B-lineage acute leukaemia (B-ALL) but rarely elucidated in acute myeloid leukaemia (AML). IKZF1 mutations...
BACKGROUND
Genetic mutations of IKZF1 have been frequently delineated in B-lineage acute leukaemia (B-ALL) but rarely elucidated in acute myeloid leukaemia (AML). IKZF1 mutations confer a poor prognosis in AML, and hotspot mutations of IKZF1, N159Y and N159S tend to occur in B-ALL and AML respectively. However, the pathogenesis of IKZF1 N159S in AML and IKZF1 lineage susceptibility are largely unknown.
METHODS
The genetic and clinical characteristics of IKZF1-mutated AML patients were evaluated. Multi-omics analysis and functional assays were performed in vitro using IKZF1 mutations knock-in AML cell lines.
RESULTS
23 (4.84%) small sequence variants of IKZF1 were identified in 475 newly diagnosed AML (non-M3) patients. Based on RNA sequencing, three classes of IKZF1-related AML were defined, including 9 patients (39.13%) with IKZF1 N159S mutations, 10 (43.47%) with CEBPA mutations and 4 others (17.39%). IKZF1 N159S may define a unique subgroup with higher HOXA/B expression and native B-cell immune fractions. Gene expression data of multiple knock-in cell lines indicate that the lymphocyte differentiation-related MME and CD44 kept high expression in IKZF1 N159Y but were downregulated in N159S. CUT&TAG sequencing showed that IKZF1 N159S reshaped the binding profiles of IKZF1. Integration analysis suggested that the pathogenesis of IKZF1 N159S may depend on the deregulation of several cofactors, such as oncogenic MYC and CPNE7 targets.
CONCLUSIONS
Collectively, we dissected the molecular spectrum and clinical features of IKZF1-related AML, which may promote an in-depth understanding of the pathogenesis, lineage susceptibility and clinical research of AML.
Topics: Leukemia, Myeloid, Acute; Humans; Ikaros Transcription Factor; Mutation; Transcriptome; Proto-Oncogene Proteins c-myc; Membrane Proteins
PubMed: 37345307
DOI: 10.1002/ctm2.1309 -
British Journal of Haematology Aug 2015Deregulated Hedgehog (Hh) signalling activity may be associated with a broad range of cancer types and hence has become an attractive target for therapeutic... (Review)
Review
Deregulated Hedgehog (Hh) signalling activity may be associated with a broad range of cancer types and hence has become an attractive target for therapeutic intervention. Although initial haematological interest focused on the therapeutic targeting of this pathway in chronic myeloid leukaemia), small molecule inhibitors targeting the Hh pathway are now being tested in a range of other myeloid disorders, including myelofibrosis, myelodysplasia and acute myeloid leukaemia. In this review we will evaluate the rationale for targeting of the Hh pathway in myeloid diseases and discuss the novel agents that have entered the clinical arena. We will discuss pre-clinical models, emerging clinical trial data, and suggest how these targeted therapies may address current unmet medical needs. Finally, we will explore potential limitations of these therapies due to the emergence of secondary resistance mechanisms and speculate on future developments within this arena.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Hedgehog Proteins; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neoplasm Proteins; Primary Myelofibrosis; Signal Transduction
PubMed: 25892100
DOI: 10.1111/bjh.13426 -
Journal of Translational Medicine Oct 2023The composition of the bone marrow immune microenvironment in patients with acute myeloid leukaemia (AML) was analysed by single-cell sequencing and the evolutionary...
BACKGROUND
The composition of the bone marrow immune microenvironment in patients with acute myeloid leukaemia (AML) was analysed by single-cell sequencing and the evolutionary role of different subpopulations of T cells in the development of AML and in driving drug resistance was explored in conjunction with E3 ubiquitin ligase-related genes.
METHODS
To elucidate the mechanisms underlying AML-NR and Ara-C resistance, we analyzed the bone marrow immune microenvironment of AML patients by integrating multiple single-cell RNA sequencing datasets. When compared to the AML disease remission (AML-CR) cohort, AML-NR displayed distinct cellular interactions and alterations in the ratios of CD4T, Treg, and CD8T cell populations.
RESULTS
Our findings indicate that the E3 ubiquitin ligase RNF149 accelerates AML progression, modifies the AML immune milieu, triggers CD8T cell dysfunction, and influences the transformation of CD8 Navie.T cells to CD8T, culminating in diminished AML responsiveness to chemotherapeutic agents. Experiments both in vivo and in vitro revealed RNF149's role in enhancing AML drug-resistant cell line proliferation and in apoptotic inhibition, fostering resistance to Ara-C.
CONCLUSION
In essence, the immune microenvironments of AML-CR and AML-NR diverge considerably, spotlighting RNF149's tumorigenic function in AML and cementing its status as a potential prognostic indicator and innovative therapeutic avenue for countering AML resistance.
Topics: Humans; Leukemia, Myeloid, Acute; Bone Marrow; Cytarabine; Drug Resistance; Ubiquitin-Protein Ligases; Tumor Microenvironment
PubMed: 37891580
DOI: 10.1186/s12967-023-04579-5