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International Journal of Molecular... Apr 2024Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the...
Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the prognosis of AML patients remains poor and there is a need for the evaluation of promising therapeutic candidates to treat the disease. The objective of this study was to evaluate the efficacy of duocarmycin Stable A (DSA) in AML cells in vitro. We hypothesized that DSA would induce DNA damage in the form of DNA double-strand breaks (DSBs) and exert cytotoxic effects on AML cells within the picomolar range. Human AML cell lines Molm-14 and HL-60 were used to perform 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), DNA DSBs, cell cycle, 5-ethynyl-2-deoxyuridine (EdU), colony formation unit (CFU), Annexin V, RNA sequencing and other assays described in this study. Our results showed that DSA induced DNA DSBs, induced cell cycle arrest at the G2M phase, reduced proliferation and increased apoptosis in AML cells. Additionally, RNA sequencing results showed that DSA regulates genes that are associated with cellular processes such as DNA repair, G2M checkpoint and apoptosis. These results suggest that DSA is efficacious in AML cells and is therefore a promising potential therapeutic candidate that can be further evaluated for the treatment of AML.
Topics: Humans; Apoptosis; Leukemia, Myeloid, Acute; Cell Proliferation; Duocarmycins; Cell Line, Tumor; DNA Breaks, Double-Stranded; HL-60 Cells; Antineoplastic Agents; Cell Cycle Checkpoints; DNA Damage
PubMed: 38673926
DOI: 10.3390/ijms25084342 -
The Lancet. Digital Health May 2024Acute leukaemias are life-threatening haematological cancers characterised by the infiltration of transformed immature haematopoietic cells in the blood and bone marrow....
Evaluation of a machine-learning model based on laboratory parameters for the prediction of acute leukaemia subtypes: a multicentre model development and validation study in France.
BACKGROUND
Acute leukaemias are life-threatening haematological cancers characterised by the infiltration of transformed immature haematopoietic cells in the blood and bone marrow. Prompt and accurate diagnosis of the three main acute leukaemia subtypes (ie acute lymphocytic leukaemia [ALL], acute myeloid leukaemia [AML], and acute promyelocytic leukaemia [APL]) is of utmost importance to guide initial treatment and prevent early mortality but requires cytological expertise that is not always available. We aimed to benchmark different machine-learning strategies using a custom variable selection algorithm to propose an extreme gradient boosting model to predict leukaemia subtypes on the basis of routine laboratory parameters.
METHODS
This multicentre model development and validation study was conducted with data from six independent French university hospital databases. Patients aged 18 years or older diagnosed with AML, APL, or ALL in any one of these six hospital databases between March 1, 2012, and Dec 31, 2021, were recruited. 22 routine parameters were collected at the time of initial disease evaluation; variables with more than 25% of missing values in two datasets were not used for model training, leading to the final inclusion of 19 parameters. The performances of the final model were evaluated on internal testing and external validation sets with area under the receiver operating characteristic curves (AUCs), and clinically relevant cutoffs were chosen to guide clinical decision making. The final tool, Artificial Intelligence Prediction of Acute Leukemia (AI-PAL), was developed from this model.
FINDINGS
1410 patients diagnosed with AML, APL, or ALL were included. Data quality control showed few missing values for each cohort, with the exception of uric acid and lactate dehydrogenase for the cohort from Hôpital Cochin. 679 patients from Hôpital Lyon Sud and Centre Hospitalier Universitaire de Clermont-Ferrand were split into the training (n=477) and internal testing (n=202) sets. 731 patients from the four other cohorts were used for external validation. Overall AUCs across all validation cohorts were 0·97 (95% CI 0·95-0·99) for APL, 0·90 (0·83-0·97) for ALL, and 0·89 (0·82-0·95) for AML. Cutoffs were then established on the overall cohort of 1410 patients to guide clinical decisions. Confident cutoffs showed two (0·14%) wrong predictions for ALL, four (0·28%) wrong predictions for APL, and three (0·21%) wrong predictions for AML. Use of the overall cutoff greatly reduced the number of missing predictions; diagnosis was proposed for 1375 (97·5%) of 1410 patients for each category, with only a slight increase in wrong predictions. The final model evaluation across both the internal testing and external validation sets showed accuracy of 99·5% for ALL diagnosis, 98·8% for AML diagnosis, and 99·7% for APL diagnosis in the confident model and accuracy of 87·9% for ALL diagnosis, 86·3% for AML diagnosis, and 96·1% for APL diagnosis in the overall model.
INTERPRETATION
AI-PAL allowed for accurate diagnosis of the three main acute leukaemia subtypes. Based on ten simple laboratory parameters, its broad availability could help guide initial therapies in a context where cytological expertise is lacking, such as in low-income countries.
FUNDING
None.
Topics: Humans; France; Machine Learning; Leukemia, Myeloid, Acute; Female; Male; Middle Aged; Adult; Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Promyelocytic, Acute; Algorithms
PubMed: 38670741
DOI: 10.1016/S2589-7500(24)00044-X -
Clinical Genetics Aug 2024Acute promyelocytic leukemia (APL) represents 5%-10% of childhood acute myeloid leukemia (AML) and is the most curable subtype of AML. Fanconi anemia (FA) is one of the... (Review)
Review
Acute promyelocytic leukemia (APL) represents 5%-10% of childhood acute myeloid leukemia (AML) and is the most curable subtype of AML. Fanconi anemia (FA) is one of the most common inherited bone marrow failure syndromes caused by biallelic pathogenic variants (PV) in specific DNA-repair genes. Biallelic PVs in FANCD1/BRCA2 (FA-D1) account for 3% of FA and are associated with early-onset leukemia and a high risk of solid tumors. We report a 4 year-old boy from non-consanguineous parents diagnosed with standard risk APL. This child had café-au-lait spots and an extra thumb remnant. Genomic sequencing revealed two PV in FANCD1/BRCA2 confirming a diagnosis of FA-D1. Chromosomal breakage studies were compatible with FA. Each parent carried one variant and had no personal history of cancer. Morphological then molecular remissions were achieved with all-trans retinoic acid and Arsenic trioxide. This patient underwent haploidentical stem cell transplant. In addition to our patient, a literature search revealed four additional patients with APL/FA, with a total of three patients with FA-D1. This raises the possibility of an association between such rare disorders. Practical management of APL in the setting of FA-D1 is discussed with an overview of current evidence and knowledge gaps.
Topics: Humans; Fanconi Anemia; Leukemia, Promyelocytic, Acute; Male; Child, Preschool; BRCA2 Protein; Genetic Predisposition to Disease
PubMed: 38658784
DOI: 10.1111/cge.14537 -
Scientific Reports Apr 2024Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in...
Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of "neutrophil-like" HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in (Ptf1aCre™; LSL-Kras) and functional WT Ptf1aCre™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.
Topics: Animals; Activins; Mice; Humans; Macrophages; Pancreatitis; Signal Transduction; Cell Movement; Neutrophil Activation; Neutrophils; Disease Models, Animal; RAW 264.7 Cells; Macrophage Activation; HL-60 Cells; Pancreatitis, Chronic; Male
PubMed: 38654064
DOI: 10.1038/s41598-024-60065-y -
Proceedings of the National Academy of... Apr 2024The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of...
The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies revealed that PML::RARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PML::RARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of , overexpression induces many of the same epigenetic and transcriptional changes as . These findings suggested that may indirectly initiate its transcriptional program by activating expression: Indeed, we demonstrated that inactivation of prior to expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PML::RARA can potentially bind and interact with each other. In turn, PML::RARA binding to DNA promotes a feed-forward transcriptional program by positively regulating expression. may therefore be required for to establish its transcriptional program.
Topics: Animals; Humans; Mice; Binding Sites; Cell Self Renewal; Chromatin; DNA; GATA2 Transcription Factor; Hematopoietic Stem Cells; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Protein Binding; Retinoic Acid Receptor alpha
PubMed: 38648485
DOI: 10.1073/pnas.2317690121 -
Journal of Hematology Apr 2024Intracerebral hemorrhage is a potentially fatal complication in patients with acute leukemia and contributing factors include thrombocytopenia and coagulopathy. Patients...
Intracerebral hemorrhage is a potentially fatal complication in patients with acute leukemia and contributing factors include thrombocytopenia and coagulopathy. Patients with acute leukemia may develop subdural hematoma (SDH) spontaneously or secondary to trauma. In patients with acute leukemia and SDH, the surgical evacuation of the hematoma causes significant morbidity and mortality. New approaches and strategies to reduce the need for surgical evacuation are needed to improve outcomes in patients with acute leukemia and intracerebral hemorrhage. We report two cases of acute SDH in patients with acute leukemia successfully treated with middle meningeal artery embolization, a minimally invasive interventional radiology technique, obviating the need for a surgical intervention. The first patient with acute promyelocytic leukemia (APL) presented with coagulopathy and developed an acute SDH after a fall. The second patient with acute myeloid leukemia presented with gum bleeding and also sustained an acute SDH after a fall. Both patients underwent middle meningeal artery embolization for treating their SDHs while actively receiving induction chemotherapy for acute leukemia. Both patients had resolution of their acute SDH and are in remission from their acute leukemia. Middle meningeal artery embolization is a very effective, and within the context of this setting, a novel, minimally invasive technique for management of SDH in acute leukemia patients, which can prevent the need for surgical interventions with its associated comorbidities and high risk of fatal outcomes in patients with acute leukemia and acute SDH.
PubMed: 38644984
DOI: 10.14740/jh1215 -
Cureus Mar 2024Considerable advances in the diagnosis and treatment of cancer have made a huge impact on morbidity and mortality from neoplastic diseases. However, cancer remains the...
Considerable advances in the diagnosis and treatment of cancer have made a huge impact on morbidity and mortality from neoplastic diseases. However, cancer remains the leading cause of death across the world. This is a retrospective study carried out at a tertiary cancer care centre (Kidwai Memorial Institute of Oncology, Bangalore) in South India. Case records of all cancer patients who died while receiving inpatient treatment between January 2022 and December 2022 under the Department of Medical Oncology were reviewed and studied. There was a total of 240 deaths. Out of these, the majority of deaths 147 (61.25%) were patients with haematological malignancies while the remaining 93 (38.75%) were patients with solid tumours. In patients with solid tumours, the majority 49 (52.7%) were in the age group of 40 to 60 years while only 18 (19.35%) patients were less than 40 years. The majority of patients were male sex i.e. 55(59.1%) and undergoing treatment with palliative intent 81 (87%). The most common organ was the lung in 21 patients (22.6%) followed by the breast while the most common system involved was the gastrointestinal tract in 28 (30.1%) patients. The most frequent cause of death was progressive disease in 72 (77.4%) while sepsis (11 patients; 11.8%) was the second most frequent cause of death in solid tumours. In haematological malignancies, also a significant number of 57 (38.8%) patients were in the age group of 40 to 60 years. Fifty-two (35.3%) patients were in the age group of 22 to 40 years. The majority were male sex (79 patients; 53.7%). About the phase of treatment, the majority of deaths 45 (30.6%) were during induction and under evaluation. Those with relapse/refractory disease were 38 (25.9%). A substantial number of patients had acute myeloid leukaemia 47 (32%) and five (3.4%) deaths were acute promyelocytic leukaemia patients. Twenty-three patients (15.6%) had acute lymphoblastic leukaemia. The most common cause of death was sepsis in 76 patients (51.7%) while intracranial bleeding was in 34 patients (23.1%). In some patients, there were multiple causes leading to death. Mortality audits are important to evaluate the services being provided at any centre. One can appreciate the lacunae in handling a particular disease or flaws in a treatment protocol or the staff delivering the treatment. Sepsis is the leading cause of death in patients with haematological malignancy; even in solid malignancy sepsis accounts for a substantial proportion of deaths and should be handled aggressively to save lives.
PubMed: 38629016
DOI: 10.7759/cureus.56296 -
Cell Death and Differentiation Jun 2024The alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered...
The alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered that PML1 is the most abundant isoform in all breast cancer subtypes, and its expression is associated with unfavorable prognosis in estrogen receptor-positive (ER+) breast cancers. PML depletion reduces cell proliferation, invasion, and stemness, while heterologous PML1 expression augments these processes and fuels tumor growth and resistance to fulvestrant, an FDA-approved drug for ER+ breast cancer, in a mouse model. Moreover, PML1, rather than the well-known tumor suppressor isoform PML4, rescues the proliferation of PML knockdown cells. ChIP-seq analysis reveals significant overlap between PML-, ER-, and Myc-bound promoters, suggesting their coordinated regulation of target gene expression, including genes involved in breast cancer stem cells (BCSCs), such as JAG1, KLF4, YAP1, SNAI1, and MYC. Loss of PML reduces BCSC-related gene expression, and exogenous PML1 expression elevates their expression. Consistently, PML1 restores the association of PML with these promoters in PML-depleted cells. We identified a novel association between PML1 and WDR5, a key component of H3K4 methyltransferase (HMTs) complexes that catalyze H3K4me1 and H3K4me3. ChIP-seq analyses showed that the loss of PML1 reduces H3K4me3 in numerous loci, including BCSC-associated gene promoters. Additionally, PML1, not PML4, re-establishes the H3K4me3 mark on these promoters in PML-depleted cells. Significantly, PML1 is essential for recruiting WDR5, MLL1, and MLL2 to these gene promoters. Inactivating WDR5 by knockdown or inhibitors phenocopies the effects of PML1 loss, reducing BCSC-related gene expression and tumorsphere formation and enhancing fulvestrant's anticancer activity. Our findings challenge the conventional understanding of PML as a tumor suppressor, redefine its role as a promoter of tumor growth in breast cancer, and offer new insights into the unique roles of PML isoforms in breast cancer.
Topics: Humans; Breast Neoplasms; Female; Kruppel-Like Factor 4; Promyelocytic Leukemia Protein; Animals; Receptors, Estrogen; Mice; Neoplastic Stem Cells; Histones; Intracellular Signaling Peptides and Proteins; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic
PubMed: 38627584
DOI: 10.1038/s41418-024-01294-6 -
Immunobiology May 2024Inducible co-stimulatory factor (ICOS) has a dual role: activating cytotoxic T cells against tumors or exacerbating immunosuppression of regulatory T cells (Tregs) to...
BACKGROUND
Inducible co-stimulatory factor (ICOS) has a dual role: activating cytotoxic T cells against tumors or exacerbating immunosuppression of regulatory T cells (Tregs) to participate in immune evasion. However, the correlation between ICOS and its co-expression with inhibitory immune checkpoints (IICs) and prognosis in acute myeloid leukemia (AML) is little known.
METHODS
The prognostic importance of ICOS and IICs in 62 bone marrow (BM) samples of de novo AML patients from our clinical center (GZFPH) was explored and then the RNA sequencing data of 155 AML patients from the Cancer Genome Atlas (TCGA) database was used for validation.
RESULTS
In both GZFPH and TCGA cohorts, high expression of ICOS was significantly associated with poor overall survival (OS) in patients with AML (P < 0.05). Importantly, co-expression of ICOS and PD-1, PD-L1, PD-L2, CTLA-4, and LAG-3 predicted poor OS in AML; among them, ICOS/PD-1 was the optimal combination of immune checkpoints (ICs). The co-expression of ICOS and PD-1 was correlated with poor OS in non-acute promyelocytic leukemia (non-APL) patients following chemotherapy. Additionally, ICOS/PD-1 was an independent OS-predicting factor (P < 0.05). Notably, a nomogram model was constructed by combining ICOS/PD-1, age, European Leukemia Net (ELN) risk stratification, and therapy to visually and personalized predict the 1-, 3-, and 5-year OS of patients with non-APL.
CONCLUSION
Increased expression of ICOS predicted poor outcomes, and ICOS/PD-1 was the optimal combination of ICs to predict outcomes in patients with AML, which might be a potential immune biomarker for designing novel AML therapy.
Topics: Humans; Inducible T-Cell Co-Stimulator Protein; Leukemia, Myeloid, Acute; Programmed Cell Death 1 Receptor; Male; Female; Prognosis; Middle Aged; Adult; Biomarkers, Tumor; Aged; Gene Expression Regulation, Leukemic
PubMed: 38615511
DOI: 10.1016/j.imbio.2024.152804 -
Molecules (Basel, Switzerland) Mar 2024In the present work, the synthesis of new ethacrynic acid () derivatives containing nitrogen heterocyclic, urea, or thiourea moieties via efficient and practical...
Design, Synthesis, Computational Studies, and Anti-Proliferative Evaluation of Novel Ethacrynic Acid Derivatives Containing Nitrogen Heterocycle, Urea, and Thiourea Moieties as Anticancer Agents.
In the present work, the synthesis of new ethacrynic acid () derivatives containing nitrogen heterocyclic, urea, or thiourea moieties via efficient and practical synthetic procedures was reported. The synthesised compounds were screened for their anti-proliferative activity against two different cancer cell lines, namely, HL60 (promyelocytic leukaemia) and HCT116 (human colon carcinoma). The results of the in vitro tests reveal that compounds -, , (-), and exhibit potent anti-proliferative activity against the HL60 cell line, with values of the percentage of cell viability ranging from 20 to 35% at 1 μM of the drug and IC values between 2.37 μM and 0.86 μM. Compounds 2 and 10 showed a very interesting anti-proliferative activity of 28 and 48% at 1 μM, respectively, against HCT116. Two -based fluorescent analogues were also synthesised and tested, showing good anti-proliferative activity. A test on the drug-likeness properties in silico of all the synthetised compounds was performed in order to understand the mechanism of action of the most active compounds. A molecular docking study was conducted on two human proteins, namely, glutathione S-transferase P1-1 (pdb:2GSS) and caspase-3 (pdb:4AU8) as target enzymes. The docking results show that compounds and exhibit significant binding modes with these enzymes. This finding provides a potential strategy towards developing anticancer agents, and most of the synthesised and newly designed compounds show good drug-like properties.
Topics: Humans; Urea; Thiourea; Ethacrynic Acid; Molecular Docking Simulation; Antineoplastic Agents; HL-60 Cells; Nitrogen
PubMed: 38611717
DOI: 10.3390/molecules29071437