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British Journal of Haematology Jan 2020Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently... (Review)
Review
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.
Topics: Adolescent; Child; Drug Resistance, Neoplasm; Epigenesis, Genetic; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Mutation
PubMed: 31804725
DOI: 10.1111/bjh.16361 -
British Journal of Haematology Jan 2020Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient-related factors,... (Review)
Review
Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient-related factors, including age, prior haematologic disorders, and comorbidities. Despite the diverse disease biology, the standard of care for remission induction therapy has changed very little since its inception in 1973. Next generation sequencing has helped to increase our knowledge of the disease pathogenesis, allowing us to develop targeted and possibly more effective treatment options. Seven new agents have been approved for the treatment of AML since 2017, all of which are directed toward a specific molecular subtype or patient population. With the advent of these therapies, a more optimal, patient-specific approach rather than the historical 'one-size fits all' model can be utilised. This review will discuss the role of these novel therapies in the remission induction setting.
Topics: Disease-Free Survival; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid, Acute; Precision Medicine; Remission Induction
PubMed: 31828798
DOI: 10.1111/bjh.16353 -
British Journal of Haematology Nov 2017Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape... (Review)
Review
Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, standard treatment options have not significantly changed during the past three decades. AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signalling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis. This review aims to provide an overview of advances in new prognostic markers, including targetable mutations that will probably guide the development and use of novel molecularly targeted therapies.
Topics: Carcinogenesis; Epigenesis, Genetic; Genes, ras; Genomics; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Mutation; Mutation Accumulation; Nuclear Proteins; Nucleophosmin; Prognosis; fms-Like Tyrosine Kinase 3
PubMed: 28653397
DOI: 10.1111/bjh.14823 -
Cells Nov 2019Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor... (Review)
Review
Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor cells, which upregulate Wnt signalling through a variety of mechanisms. Other mechanisms of Wnt activation in AML have been described such as Wnt antagonist inactivation through promoter methylation. Wnt signalling is necessary for the maintenance of leukaemic stem cells. Several molecules involved in or modulating Wnt signalling have a prognostic value in AML. These include: β-catenin, LEF-1, phosphorylated-GSK3β, PSMD2, PPARD, XPNPEP, sFRP2, RUNX1, AXIN2, PCDH17, CXXC5, LLGL1 and PTK7. Targeting Wnt signalling for tumour eradication is an approach that is being explored in haematological and solid tumours. A number of preclinical studies confirms its feasibility, albeit, so far no reliable clinical trial data are available to prove its utility and efficacy.
Topics: Animals; Biomarkers; Disease Management; Disease Susceptibility; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Prognosis; Wnt Signaling Pathway
PubMed: 31703382
DOI: 10.3390/cells8111403 -
British Journal of Haematology Jan 2020Modern management of acute myeloid leukaemia (AML) relies on the integration of phenotypic and genetic data to assign classification, establish prognosis, enhance... (Review)
Review
Modern management of acute myeloid leukaemia (AML) relies on the integration of phenotypic and genetic data to assign classification, establish prognosis, enhance monitoring and guide treatment. The prism through which we can now disperse a patient's leukaemia, interpret and apply our understanding has fundamentally changed since the completion of the first whole-genome sequencing (WGS) of an AML patient in 2008 and where possible, many clinicians would now prefer to delay treatment decisions until the karyotype and genetic status of a new patient is known. The success of global sequencing initiatives such as The Cancer Genome Atlas (TCGA) have brought us significantly closer to cataloguing the full spectrum of coding mutations involved in human malignancy. Indeed, genetic capability has raced ahead of our capacity to apply much of this knowledge into clinical practice and we are in the peculiar position of having routine access to genetic information on an individual patient's leukaemia that cannot be reliably interpreted or utilised. This is a measure of how rapid the progress has been, and this rate of change is likely to continue into the foreseeable future as research intensifies on the non-coding genome and the epigenome, as we scrutinise disease at a single cell level, and as initiatives like Beat AML and the Harmony Alliance progress. In this review, we will examine how interrogation of the coding genome is revolutionising our understanding of AML and improving our ability to underscore differences between paediatric and adult onset, sporadic and inherited forms of disease. We will look at how this knowledge is informing improvements in outcome prediction and the development of novel treatments, bringing us a step closer to personalised therapy for myeloid malignancy.
Topics: Databases, Genetic; Epigenome; Genome, Human; Humans; Leukemia, Myeloid, Acute; Mutation; Whole Genome Sequencing
PubMed: 31863468
DOI: 10.1111/bjh.16356 -
Journal of Investigative Medicine : the... Dec 2018The treatment of acute myeloid leukemia (AML) has remained relatively unchanged for the past 3-4 decades with generally poor outcomes, especially in elderly populations... (Review)
Review
The treatment of acute myeloid leukemia (AML) has remained relatively unchanged for the past 3-4 decades with generally poor outcomes, especially in elderly populations unfit for intensive therapy. Recent advancements, however, have identified several cytogenetic and molecular markers that have not only improved prognostication but have also led to the development of several new targeted therapies for specific subpopulations. In 2017, the US Food and Drug Administration approved four new treatments with indications for fms like tyrosine kinase 3 (FLT3)-mutated AML (midostaurin), newly diagnosed or relapsed/refractory CD33+AML (gemtuzumab ozogamicin), newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (CPX-351) and relapsed/refractory AML with an isocitrate dehydrogenase (IDH)2 mutation (enasidenib). These newly approved therapies have demonstrated improved response in their target populations in several pivotal clinical trials with some also demonstrating improved overall survival. Additional novel therapies in development for AML include agents that target B cell lymphoma 2, FLT3, IDH1, the ubiquitination pathway, as well as cell therapy using engineered T cells with chimeric antigen receptors. This review provides a summary of the four newly approved therapies for AML, as well as several promising therapies currently in development.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Drug Development; Humans; Leukemia, Myeloid, Acute
PubMed: 30127098
DOI: 10.1136/jim-2018-000807 -
Clinical Medicine (London, England) May 2022Acute leukaemia is characterised by uncontrolled expansion of immature leukocytes, either myeloid or lymphoid progenitors, leading to acute myeloid leukaemia (AML) and...
Acute leukaemia is characterised by uncontrolled expansion of immature leukocytes, either myeloid or lymphoid progenitors, leading to acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL), respectively. If left untreated, it is life-threatening and can lead to death within weeks. When acute leukaemia is suspected, urgent haematology input should be sought. Appropriate investigations are needed promptly to confirm diagnosis and start treatment. A multidisciplinary approach is vital to ensure appropriate management.
Topics: Acute Disease; Humans; Leukemia, Myeloid, Acute
PubMed: 35584840
DOI: 10.7861/clinmed.2022-0149 -
British Journal of Haematology Nov 2012Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has... (Review)
Review
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.
Topics: Adolescent; Child; Child, Preschool; Humans; Leukemia, Myeloid, Acute; Prognosis; Young Adult
PubMed: 22966788
DOI: 10.1111/bjh.12040 -
British Journal of Haematology Aug 2019Despite significant advances in the treatment of myeloid malignancies, many patients become resistant to therapy and ultimately succumb to their disease. Accumulating... (Review)
Review
Despite significant advances in the treatment of myeloid malignancies, many patients become resistant to therapy and ultimately succumb to their disease. Accumulating evidence over the past several years has suggested that the inadequacy of many leukaemia therapies results from their failure to target the leukaemic stem cell (LSC). For this reason, the LSC population currently represents the most critical target in the treatment of myeloid malignancies. However, while LSCs are ideal targets in the treatment of these diseases, they are also the most difficult population to target. This is due to both their heterogeneity within the LSC population, and also their phenotypic similarities with normal haematopoietic stem cells. This review will highlight the current landscape surrounding LSC biology in myeloid malignancies, with a focus on altered energy metabolism, and how that knowledge is being translated into clinical advances for the treatment of chronic and acute myeloid leukaemia and myelodysplastic syndromes.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Clinical Trials as Topic; Drug Resistance, Neoplasm; Energy Metabolism; Hematopoiesis; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes; Neoplastic Stem Cells; Signal Transduction; Treatment Outcome
PubMed: 31236939
DOI: 10.1111/bjh.16074 -
Current Opinion in Hematology Mar 2021In the past decade, numerous studies analysing the genome and transcriptome of large cohorts of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients... (Review)
Review
PURPOSE OF REVIEW
In the past decade, numerous studies analysing the genome and transcriptome of large cohorts of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients have substantially improved our knowledge of the genetic landscape of these diseases with the identification of heterogeneous constellations of germline and somatic mutations with prognostic and therapeutic relevance. However, inclusion of integrated genetic data into classification schema is still far from a reality. The purpose of this review is to summarize recent insights into the prevalence, pathogenic role, clonal architecture, prognostic impact and therapeutic management of genetic alterations across the spectrum of myeloid malignancies.
RECENT FINDINGS
Recent multiomic-studies, including analysis of genetic alterations at the single-cell resolution, have revealed a high heterogeneity of lesions in over 200 recurrently mutated genes affecting disease initiation, clonal evolution and clinical outcome. Artificial intelligence and specifically machine learning approaches have been applied to large cohorts of AML and MDS patients to define in an unbiased manner clinically meaningful disease patterns including, disease classification, prognostication and therapeutic vulnerability, paving the way for future use in clinical practice.
SUMMARY
Integration of genomic, transcriptomic, epigenomic and clinical data coupled to conventional and machine learning approaches will allow refined leukaemia classification and risk prognostication and will identify novel therapeutic targets for these still high-risk leukaemia subtypes.
Topics: Clinical Decision-Making; Clonal Evolution; Disease Management; Epigenomics; Genetic Association Studies; Genetic Predisposition to Disease; Genomics; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Prognosis; Single-Cell Analysis; Treatment Outcome
PubMed: 33427759
DOI: 10.1097/MOH.0000000000000629