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Experimental Hematology May 2021RUNX3, a transcription factor, has been implicated as a tumor suppressor in various cancers, including hematological malignancies; however, recent studies revealed an... (Review)
Review
RUNX3, a transcription factor, has been implicated as a tumor suppressor in various cancers, including hematological malignancies; however, recent studies revealed an oncogenic function of RUNX3 in the pathogenesis of myeloid malignancies, such as myelodysplastic syndrome and acute myeloid leukemia. In contrast to the high frequency of mutations in the RUNX1 gene, deletion of and loss-of-function mutations in RUNX3 are rarely detected in patients with hematopoietic malignancies. Although RUNX3 is expressed in normal hematopoietic stem and progenitor cells, its expression decreases with aging in humans. The loss of Runx3 did not result in the development of lethal hematological diseases in mice despite the expansion of myeloid cells. Therefore, RUNX3 does not appear to initiate the transformation of normal hematopoietic stem cells. However, the overexpression of RUNX3 inhibits the expression and transcriptional function of the RUNX1 gene, but activates the expression of key oncogenic pathways, such as MYC, resulting in the transformation of premalignant stem cells harboring a driver genetic mutation. We herein discuss the mechanisms by which RUNX3 is activated and how RUNX3 exerts oncogenic effects on the cellular function of and transcriptional program in premalignant stem cells to drive myeloid transformation.
Topics: Animals; Cell Transformation, Neoplastic; Core Binding Factor Alpha 3 Subunit; Gene Expression Regulation, Neoplastic; Hematopoiesis; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes; Myeloid Cells
PubMed: 33600870
DOI: 10.1016/j.exphem.2021.02.005 -
American Society of Clinical Oncology... Apr 2022Recent advances in acute myeloid leukemia biology and drug development have transformed the therapeutic landscape for patients diagnosed with this disease. By harnessing... (Review)
Review
Recent advances in acute myeloid leukemia biology and drug development have transformed the therapeutic landscape for patients diagnosed with this disease. By harnessing insights from the study of the molecular pathogenesis of the disease, the acute myeloid leukemia treatment armamentarium now extends beyond conventional cytotoxic agents to include targeted therapies, and immunotherapeutics, with multiple novel modalities under investigation. During the past 5 years, recent drug approvals have also focused attention on disease scenarios and patient populations for whom newer therapies might be deployed. In this review, we highlight select acute myeloid leukemia therapies in the frontline setting through the lens of both disease and patient-related factors. Particular emphasis is placed on the assessment of patient fitness, as contemporary acute myeloid leukemia therapy decisions largely hinge on the determination of whether intensive chemotherapy is suitable for a patient. Additionally, we detail scenarios and areas of controversy wherein disease biology may inspire a reframing of traditional intensive treatment philosophies, regardless of patient fitness. Lastly, we provide an overview of emerging agents that are being investigated in the relapsed/refractory setting.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Myeloid, Acute; Remission Induction
PubMed: 35658497
DOI: 10.1200/EDBK_349605 -
International Journal of Molecular... Feb 2024Minimal residual disease (MRD) is of major importance in onco-hematology, particularly in acute myeloid leukemia (AML). MRD measures the amount of leukemia cells... (Review)
Review
Minimal residual disease (MRD) is of major importance in onco-hematology, particularly in acute myeloid leukemia (AML). MRD measures the amount of leukemia cells remaining in a patient after treatment, and is an essential tool for disease monitoring, relapse prognosis, and guiding treatment decisions. Patients with a negative MRD tend to have superior disease-free and overall survival rates. Considerable effort has been made to standardize MRD practices. A variety of techniques, including flow cytometry and molecular methods, are used to assess MRD, each with distinct strengths and weaknesses. MRD is recognized not only as a predictive biomarker, but also as a prognostic tool and marker of treatment efficacy. Expected advances in MRD assessment encompass molecular techniques such as NGS and digital PCR, as well as optimization strategies such as unsupervised flow cytometry analysis and leukemic stem cell monitoring. At present, there is no perfect method for measuring MRD, and significant advances are expected in the future to fully integrate MRD assessment into the management of AML patients.
Topics: Humans; Neoplasm, Residual; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Recurrence; Flow Cytometry
PubMed: 38396825
DOI: 10.3390/ijms25042150 -
Leukemia Dec 2021Children with Down syndrome are at an elevated risk of leukemia, especially myeloid leukemia (ML-DS). This malignancy is frequently preceded by transient abnormal... (Review)
Review
Children with Down syndrome are at an elevated risk of leukemia, especially myeloid leukemia (ML-DS). This malignancy is frequently preceded by transient abnormal myelopoiesis (TAM), which is self-limited expansion of fetal liver-derived megakaryocyte progenitors. An array of international studies has led to consensus in treating ML-DS with reduced-intensity chemotherapy, leading to excellent outcomes. In addition, studies performed in the past 20 years have revealed many of the genetic and epigenetic features of the tumors, including GATA1 mutations that are arguably associated with all cases of both TAM and ML-DS. Despite these advances in understanding the clinical and biological aspects of ML-DS, little is known about the mechanisms of relapse. Upon relapse, patients face a poor outcome, and there is no consensus on treatment. Future studies need to be focused on this challenging aspect of leukemia in children with DS.
Topics: Down Syndrome; GATA1 Transcription Factor; Humans; Leukemia, Myeloid; Mutation
PubMed: 34518645
DOI: 10.1038/s41375-021-01414-y -
The International Journal of... Aug 2021Acute myeloid leukemia (AML) is characterized by the disruption of myeloid differentiation and accumulation of blast cells in the bone marrow. While AML patients respond... (Review)
Review
Acute myeloid leukemia (AML) is characterized by the disruption of myeloid differentiation and accumulation of blast cells in the bone marrow. While AML patients respond favorably to induction chemotherapy, long-term outcomes remain poor due to a high rate of chemoresistance. Advances with targeted therapies, which can be used in combination with conventional chemotherapy, have expanded therapeutic options for patients. However, remission is often short-lived and followed by disease relapse and drug resistance. Therefore, there is a substantial need to improve treatment options by identifying novel molecular and cellular targets that regulate AML chemosensitivity. Membrane scaffolds such as the tetraspanin family of proteins often serve as signaling mediators, translating extracellular signaling cues into intracellular signaling cascades. In this review, we discuss the conventional and targeted treatment strategies for AML and review chemoresistance mechanisms with a focus on the tetraspanin family of membrane scaffold proteins.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Tetraspanins
PubMed: 34174403
DOI: 10.1016/j.biocel.2021.106029 -
Journal of Cellular and Molecular... Jun 2023Perturbations in autophagy, apoptosis and differentiation have greatly affected the progression and therapy of acute myeloid leukaemia (AML). The role of X-linked...
Perturbations in autophagy, apoptosis and differentiation have greatly affected the progression and therapy of acute myeloid leukaemia (AML). The role of X-linked inhibitor of apoptosis (XIAP)-related autophagy remains unclear in AML therapeutics. Here, we found that XIAP was highly expressed and associated with poor overall survival in patients with AML. Furthermore, pharmacologic inhibition of XIAP using birinapant or XIAP knockdown via siRNA impaired the proliferation and clonogenic capacity by inducing autophagy and apoptosis in AML cells. Intriguingly, birinapant-induced cell death was aggravated in combination with ATG5 siRNA or an autophagy inhibitor spautin-1, suggesting that autophagy may be a pro-survival signalling. Spautin-1 further enhanced the ROS level and myeloid differentiation in THP-1 cells treated with birinapant. The mechanism analysis showed that XIAP interacted with MDM2 and p53, and XIAP inhibition notably downregulated p53, substantially increased the AMPKα1 phosphorylation and downregulated the mTOR phosphorylation. Combined treatment using birinapant and chloroquine significantly retarded AML progression in both a subcutaneous xenograft model injected with HEL cells and an orthotopic xenograft model injected intravenously with C1498 cells. Collectively, our data suggested that XIAP inhibition can induce autophagy, apoptosis and differentiation, and combined inhibition of XIAP and autophagy may be a promising therapeutic strategy for AML.
Topics: Humans; Apoptosis; Autophagy; Cell Differentiation; Cell Line, Tumor; Leukemia, Myeloid, Acute; RNA, Small Interfering; Tumor Suppressor Protein p53; X-Linked Inhibitor of Apoptosis Protein
PubMed: 37154878
DOI: 10.1111/jcmm.17765 -
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 -
Current Oncology Reports Apr 2024This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute... (Review)
Review
PURPOSE OF REVIEW
This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute myeloid leukemia (AML).
RECENT FINDINGS
Over the course of the last 5-6 years, several targeted therapies have been approved by the FDA, for the treatment of both newly diagnosed as well as relapsed/refractory AML. These novel therapeutics, as well as several others currently under investigation, have demonstrated activity in AML and have improved outcomes for many patients. Patient outcomes in AML have slowly improved over time, though for many patients, particularly elderly patients or those with relapsed/refractory disease, mortality remains very high. With the identification of several molecular/genetic drivers and protein targets and development of therapeutics which leverage those mechanisms to target leukemic cells, outcomes for patients with AML have improved and continue to improve significantly.
Topics: Humans; Aged; Leukemia, Myeloid, Acute
PubMed: 38502417
DOI: 10.1007/s11912-024-01503-y -
International Journal of Molecular... Sep 2019Acute myeloid leukemia (AML) is a heterogeneous disease that is characterized by distinct cytogenetic or genetic abnormalities. Recent discoveries in cancer epigenetics... (Review)
Review
Acute myeloid leukemia (AML) is a heterogeneous disease that is characterized by distinct cytogenetic or genetic abnormalities. Recent discoveries in cancer epigenetics demonstrated a critical role of epigenetic dysregulation in AML pathogenesis. Unlike genetic alterations, the reversible nature of epigenetic modifications is therapeutically attractive in cancer therapy. DNA methylation is an epigenetic modification that regulates gene expression and plays a pivotal role in mammalian development including hematopoiesis. DNA methyltransferases (DNMTs) and Ten-eleven-translocation (TET) dioxygenases are responsible for the dynamics of DNA methylation. Genetic alterations of DNMTs or TETs disrupt normal hematopoiesis and subsequently result in hematological malignancies. Emerging evidence reveals that the dysregulation of DNA methylation is a key event for AML initiation and progression. Importantly, aberrant DNA methylation is regarded as a hallmark of AML, which is heralded as a powerful epigenetic marker in early diagnosis, prognostic prediction, and therapeutic decision-making. In this review, we summarize the current knowledge of DNA methylation in normal hematopoiesis and AML pathogenesis. We also discuss the clinical implications of DNA methylation and the current therapeutic strategies of targeting DNA methylation in AML therapy.
Topics: Animals; Biomarkers, Tumor; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Prognosis
PubMed: 31527484
DOI: 10.3390/ijms20184576 -
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