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Seminars in Cancer Biology Feb 2020The development of a myeloid neoplasm is a step-wise process that originates from leukemic stem cells (LSC) and includes pre-leukemic stages, overt leukemia and a... (Review)
Review
The development of a myeloid neoplasm is a step-wise process that originates from leukemic stem cells (LSC) and includes pre-leukemic stages, overt leukemia and a drug-resistant terminal phase. Organ-invasion may occur in any stage, but is usually associated with advanced disease and a poor prognosis. Sometimes, extra-medullary organ invasion shows a metastasis-like or even sarcoma-like destructive growth of neoplastic cells in local tissue sites. Examples are myeloid sarcoma, mast cell sarcoma and localized blast phase of chronic myeloid leukemia. So far, little is known about mechanisms underlying re-distribution and extramedullary dissemination of LSC in myeloid neoplasms. In this article, we discuss mechanisms through which LSC can mobilize out of the bone marrow niche, can transmigrate from the blood stream into extramedullary organs, can invade local tissue sites and can potentially create or support the formation of local stem cell niches. In addition, we discuss strategies to interfere with LSC expansion and organ invasion by targeted drug therapies.
Topics: Animals; Biomarkers; Bone Marrow; Cell Communication; Cell Movement; Humans; Immunophenotyping; Leukemia, Myeloid; Neoplasm Staging; Neoplastic Stem Cells; Phenotype; Recurrence; Transendothelial and Transepithelial Migration; Tumor Microenvironment
PubMed: 31408723
DOI: 10.1016/j.semcancer.2019.07.025 -
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 -
Blood Jan 2022
Topics: Humans; Leukemia, Myeloid, Acute; Protein Kinase Inhibitors
PubMed: 35024808
DOI: 10.1182/blood.2021013618 -
Scientific Reports Dec 2023The heterogeneity of acute myeloid leukemia (AML), a complex hematological malignancy, is caused by mutations in myeloid cells affecting their differentiation and...
The heterogeneity of acute myeloid leukemia (AML), a complex hematological malignancy, is caused by mutations in myeloid cells affecting their differentiation and proliferation. Thus, various cytogenetic alterations in AML cells may be characterized by a unique metabolome and require different treatment approaches. In this study, we performed untargeted metabolomics to assess metabolomics differences between AML patients and healthy controls, AML patients with different treatment outcomes, AML patients in different risk groups based on the 2017 European LeukemiaNet (ELN) recommendations for the diagnosis and management of AML, AML patients with and without FLT3-ITD mutation, and a comparison between patients with FLT3-ITD, CBF-AML (Core binding factor acute myelogenous leukemia), and MLL AML (mixed-lineage leukemia gene) in comparison to control subjects. Analyses were performed in serum samples using liquid chromatography coupled with mass spectrometry (LC-MS). The obtained metabolomics profiles exhibited many alterations in glycerophospholipid and sphingolipid metabolism and allowed us to propose biomarkers based on each of the above assessments as an aid for diagnosis and eventual classification, allowing physicians to choose the best-suited treatment approach. These results highlight the application of LC-MS-based metabolomics of serum samples as an aid in diagnostics and a potential minimally invasive prognostic tool for identifying various cytogenetic and treatment outcomes of AML.
Topics: Humans; Leukemia, Myeloid, Acute; Prognosis; Treatment Outcome; Mutation; Risk Factors; fms-Like Tyrosine Kinase 3
PubMed: 38071228
DOI: 10.1038/s41598-023-48970-0 -
Blood Feb 2023
Topics: Humans; Complement C1q; Macrophages; Recurrence; Leukemia, Myeloid, Acute
PubMed: 36795452
DOI: 10.1182/blood.2022018785 -
Blood May 2020Current objectives regarding treatment of acute myeloid leukemia (AML) include achieving complete remission (CR) by clinicopathological criteria followed by... (Review)
Review
Current objectives regarding treatment of acute myeloid leukemia (AML) include achieving complete remission (CR) by clinicopathological criteria followed by interrogation for the presence of minimal/measurable residual disease (MRD) by molecular genetic and/or flow cytometric techniques. Although advances in molecular genetic technologies have enabled highly sensitive detection of AML-associated mutations and translocations, determination of MRD is complicated by the fact that many treated patients have persistent clonal hematopoiesis (CH) that may not reflect residual AML. CH detected in AML patients in CR includes true residual or early recurrent AML, myelodysplastic syndrome or CH that is ancestral to the AML, and independent or newly emerging clones of uncertain leukemogenic potential. Although the presence of AML-related mutations has been shown to be a harbinger of relapse in multiple studies, the significance of other types of CH is less well understood. In patients who undergo allogeneic hematopoietic cell transplantation (HCT), post-HCT clones can be donor-derived and in some cases engender a new myeloid neoplasm that is clonally unrelated to the recipient's original AML. In this article, we discuss the spectrum of CH that can be detected in treated AML patients, propose terminology to standardize nomenclature in this setting, and review clinical data and areas of uncertainty among the various types of posttreatment hematopoietic clones.
Topics: Clonal Hematopoiesis; Diagnostic Techniques and Procedures; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Medical Oncology; Neoplasm, Residual; Prognosis; Remission Induction; Transplantation Conditioning; Transplantation, Homologous
PubMed: 32232484
DOI: 10.1182/blood.2019004770 -
Leukemia Research Jan 2022Acute Myeloid Leukemia (AML) represents 1 % of all new cancer diagnosis made annually in the US and has a five-year survival of 30 %. Traditional treatment includes... (Review)
Review
Acute Myeloid Leukemia (AML) represents 1 % of all new cancer diagnosis made annually in the US and has a five-year survival of 30 %. Traditional treatment includes aggressive induction therapy followed by consolidation therapy that may include a hematopoietic stem cell transplant (HSCT). Thus far, HSCT remains the only potentially curative therapy for many patients with AML owing to the graft-versus-leukemia effect elicited by this treatment. The use of novel therapies, specifically immunotherapy, in the treatment of AML has been limited by the lack of appropriate target antigens, therapy associated toxicities and variable success with treatment. Antigenic variability on leukemia cells and the sharing of antigens by malignant and non-malignant cells makes the identification of appropriate antigens problematic. While studies with immunotherapeutic agents are underway, prior investigations have demonstrated a mixed response with some studies prematurely discontinued due to associated toxicities. This review presents a discussion of the envisioned role of immunotherapy in the treatment of AML in the setting of mixed therapeutic success and potentially lethal toxicities.
Topics: Acute Disease; Animals; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Immunotherapy; Leukemia, Myeloid; Prognosis; Recurrence; Transplantation, Homologous; Treatment Outcome
PubMed: 34864447
DOI: 10.1016/j.leukres.2021.106732 -
International Journal of Molecular... Feb 2023Mutations in also known as nucleophosmin-1, B23, NO38, or numatrin, are seen in approximately one-third of patients with acute myeloid leukaemia (AML). A plethora of... (Review)
Review
Mutations in also known as nucleophosmin-1, B23, NO38, or numatrin, are seen in approximately one-third of patients with acute myeloid leukaemia (AML). A plethora of treatment strategies have been studied to determine the best possible approach to curing -mutated AML. Here, we introduce the structure and function of NPM1 and describe the application of minimal residual disease (MRD) monitoring using molecular methods by means of quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), next-generation sequencing (NGS), and cytometry by time of flight (CyTOF) to target -mutated AML. Current drugs, now regarded as the standard of care for AML, as well as potential drugs still under development, will also be explored. This review will focus on the role of targeting aberrant pathways such as BCL-2 and SYK; as well as epigenetic regulators (RNA polymerase), DNA intercalators (topoisomerase II), menin inhibitors, and hypomethylating agents. Aside from medication, the effects of stress on AML presentation have been reported, and some possible mechanisms outlined. Moreover, targeted strategies will be briefly discussed, not only for the prevention of abnormal trafficking and localisation of cytoplasmic NPM1 but also for the elimination of mutant NPM1 proteins. Lastly, the advancement of immunotherapy such as targeting CD33, CD123, and PD-1 will be mentioned.
Topics: Humans; Leukemia, Myeloid, Acute; Mutation; Nuclear Proteins; Nucleophosmin; Polymerase Chain Reaction
PubMed: 36834572
DOI: 10.3390/ijms24043161 -
European Journal of Immunology Jan 2022Acute myeloid leukemia (AML) is a highly aggressive disease with high relapse and mortality rates. Recent years have shown a surge in novel therapeutic development for... (Review)
Review
Acute myeloid leukemia (AML) is a highly aggressive disease with high relapse and mortality rates. Recent years have shown a surge in novel therapeutic development for AML, both in clinical and preclinical stages. These developments include targeted therapies based on AML-specific molecular signatures as well as more general immune modulation and vaccination studies. In this review, we will explore the evolving arena of AML therapy and suggest some intriguing connections between immune system modulation and targeted therapy. Improved understanding of the immune system involvement in various stages of the disease and the crosstalk between immune effectors, targeted therapy, and AML cells can provide a better framework for designing the next generation of AML therapies.
Topics: Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy
PubMed: 34648664
DOI: 10.1002/eji.202048945