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Frontiers in Immunology 2024γδ T cells recognize and exert cytotoxicity against tumor cells. They are also considered potential immune cells for immunotherapy. Our previous study revealed that...
INTRODUCTION
γδ T cells recognize and exert cytotoxicity against tumor cells. They are also considered potential immune cells for immunotherapy. Our previous study revealed that the altered expression of immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on γδ T cells may result in immunosuppression and is possibly associated with a poor overall survival in acute myeloid leukemia (AML). However, whether γδ T-cell memory subsets are predominantly involved and whether they have a relationship with clinical outcomes in patients with AML under the age of 65 remain unclear.
METHODS
In this study, we developed a multicolor flow cytometry-based assay to monitor the frequency and distribution of γδ T-cell subsets, including central memory γδ T cells (T γδ), effector memory γδ T cells (T γδ), and T expressing CD45RA (T γδ), in peripheral blood from 30 young (≤65 years old) patients with newly diagnosed non-acute promyelocytic leukemia (also known as M3) AML (AMLy-DN), 14 young patients with AML in complete remission (AMLy-CR), and 30 healthy individuals (HIs).
RESULTS
Compared with HIs, patients with AMLy-DN exhibited a significantly higher differentiation of γδ T cells, which was characterized by decreased T γδ cells and increased T γδ cells. A generally higher TIGIT expression was observed in γδ T cells and relative subsets in patients with AMLy-DN, which was partially recovered in patients with AMLy-CR. Furthermore, 17 paired bone marrow from patients with AMLy-DN contained higher percentages of γδ and TIGIT+ γδ T cells and a lower percentage of T γδ T cells. Multivariate logistic regression analyses revealed the association of high percentage of TIGIT+ T γδ T cells with an increased risk of poor induction chemotherapy response.
CONCLUSIONS
In this study, we investigated the distribution of γδ T cells and their memory subsets in patients with non-M3 AML and suggested TIGIT+ T γδ T cells as potential predictive markers of induction chemotherapy response.
Topics: Humans; Receptors, Immunologic; Male; Female; Adult; Middle Aged; Prognosis; Receptors, Antigen, T-Cell, gamma-delta; Young Adult; Aged; Memory T Cells; T-Lymphocyte Subsets; Leukemia, Myeloid, Acute; Immunologic Memory; Leukemia, Promyelocytic, Acute; Immunophenotyping
PubMed: 38711501
DOI: 10.3389/fimmu.2024.1321126 -
Communications Biology May 2024Golgin tethers are known to mediate vesicular transport in the secretory pathway, whereas it is relatively unknown whether they may mediate cellular stress response...
Golgin tethers are known to mediate vesicular transport in the secretory pathway, whereas it is relatively unknown whether they may mediate cellular stress response within the cell. Here, we describe a cellular stress response during heat shock stress via SUMOylation of a Golgin tether, Golgin45. We found that Golgin45 is a SUMOylated Golgin via SUMO1 under steady state condition. Upon heat shock stress, the Golgin enters the nucleus by interacting with Importin-β2 and gets further modified by SUMO3. Importantly, SUMOylated Golgin45 appears to interact with PML and SUMO-deficient Golgin45 mutant functions as a dominant negative for PML-NB formation during heat shock stress, suppressing transcription of lipid metabolism genes. These results indicate that Golgin45 may play a role in heat stress response by transcriptional regulation of lipid metabolism genes in SUMOylation-dependent fashion.
Topics: Sumoylation; Humans; Lipid Metabolism; Heat-Shock Response; Gene Expression Regulation; Promyelocytic Leukemia Protein; HeLa Cells; SUMO-1 Protein; Small Ubiquitin-Related Modifier Proteins; HEK293 Cells; Transcription, Genetic; beta Karyopherins; Ubiquitins
PubMed: 38710927
DOI: 10.1038/s42003-024-06232-3 -
Journal of Ginseng Research May 202420(S)-ginsenoside Rh2(GRh2), an effective natural histone deacetylase inhibitor, can inhibit acute myeloid leukemia (AML) cell proliferation. Lactate regulated histone...
BACKGROUND
20(S)-ginsenoside Rh2(GRh2), an effective natural histone deacetylase inhibitor, can inhibit acute myeloid leukemia (AML) cell proliferation. Lactate regulated histone lactylation, which has different temporal dynamics from acetylation. However, whether the high level of lactylation modification that we first detected in acute promyelocytic leukemia (APL) is associated with all-trans retinoic acid (ATRA) resistance has not been reported. Furthermore, Whether GRh2 can regulate lactylation modification in ATRA-resistant APL remains unknown.
METHODS
Lactylation and METTL3 expression levels in ATRA-sensitive and ATRA-resistant APL cells were detected by Western blot analysis, qRT-PCR and CO-IP. Flow cytometry (FCM) and APL xenograft mouse models were used to determine the effect of METTL3 and GRh2 on ATRA-resistance.
RESULTS
Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3.
CONCLUSIONS
This study suggests that lactylation-modified METTL3 could provide a promising strategy for ameliorating ATRA-resistance in APL, and GRh2 could act as a potential lactylation-modified METTL3 inhibitor to ameliorate ATRA-resistance in APL.
PubMed: 38707638
DOI: 10.1016/j.jgr.2023.12.003 -
Cureus Apr 2024Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, trastuzumab is associated with cardiotoxicity....
Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, trastuzumab is associated with cardiotoxicity. It manifests with an asymptomatic reduction of left ventricular ejection fraction (LVEF) and is reversible after discontinuation. Trastuzumab-induced new-onset acute decompensated heart failure is rare (0.5%). We report a case of a 54-year-old woman who received anthracycline (idarubicin, accumulated dose 400 mg/m doxorubicin equivalent) for her acute promyelocytic leukocyte 10 years ago, had no relevant comorbidities or other pre-existing cardiovascular diseases, had maintained normal cardiac function, presenting with new-onset dyspnea at rest and bilateral lower extremities swelling 12 weeks after receiving trastuzumab induction chemotherapy for her newly diagnosed early stage HER2-positive breast cancer. Chest X-ray showed severe pulmonary edema. Echocardiography revealed diffuse left ventricular hypokinesis with LVEF 5%. After other possible etiology of cardiomyopathy, including ischemia, infection, substance, or radiation, were excluded by extensive cardiomyopathy workup, a diagnosis of trastuzumab-induced cardiotoxicity was established. Trastuzumab was discontinued, and the patient's symptom was improved with furosemide. Guildline-directed medical therapy was gradually maximized over three months. Repeat transthoracic echocardiography (TTE) at one-year follow-up after the initial diagnosis shows LVEF 33%, and the patient was referred to an advanced heart failure clinic. This case report demonstrated a rare catastrophic cardiac toxicity effect of trastuzumab and its potential association with remote exposure to anthracycline. Studies have investigated the cardiotoxicity in the concurrent use of trastuzumab and anthracycline therapy. However, how trastuzumab affected patients who were exposed to anthracycline for more than eight years had remained unreported. To our knowledge, no previous detailed case report has described the same clinical scenario as in this case. The case also demonstrates the limitation of the commonly used cardio-oncology cardiovascular risk assessment tool and highlights the importance of individualized cardiovascular risk stratification when deciding on chemotherapy plans.
PubMed: 38707046
DOI: 10.7759/cureus.59172 -
Signal Transduction and Targeted Therapy May 2024Coinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed... (Randomized Controlled Trial)
Randomized Controlled Trial
Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia: a multicenter, randomized, open-label, phase 3 trial.
Coinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed promising results in previous reports, but the efficiency of haplo-cord HCT in acute myeloid leukemia (AML) still lacks sufficient evidence. This multicenter, randomized, phase 3 trial (ClinicalTrials.gov NCT03719534) aimed to assess the efficacy and safety of haplo-cord HCT in AML patients. A total of 268 eligible patients aged 18-60 years, diagnosed with measurable residual disease in AML (excluding acute promyelocytic leukemia), with available haploidentical donors and suitable for allotransplantation, were randomly allocated (1:1) to receive haplo-cord HCT (n = 134) or haplo-HCT (n = 134). The 3-year overall survival (OS) was the primary endpoint in this study. Overall median follow-up was 36.50 months (IQR 24.75-46.50). The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group (80.5%, 95% confidence interval [CI]: 73.7-87.9 vs. 67.8% 95% CI 60.0-76.5, p = 0.013). Favorable progression-free survival (70.3%, 95% CI 62.6-78.8 vs. 57.6%, 95% CI 49.6-67.0, p = 0.012) and cumulative incidence of relapse (12.1%, 95% CI 12.0-12.2 vs. 30.3%, 95% CI 30.1-30.4, p = 0.024) were observed in haplo-cord HCT group. Grade 3-4 adverse events (AEs) within two years posttransplantation in the two groups were similar. Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery (p = 0.026) and increased T-cell reconstitution in the early period posttransplantation. Haplo-cord HCT can improve OS in AML patients without excessive AEs, which may exert additional benefits for recipients of haplo-HCT.
Topics: Humans; Adult; Leukemia, Myeloid, Acute; Male; Female; Middle Aged; Hematopoietic Stem Cell Transplantation; Cord Blood Stem Cell Transplantation; Adolescent; Transplantation, Haploidentical; Young Adult
PubMed: 38705885
DOI: 10.1038/s41392-024-01820-5 -
Oncology Letters Jun 2024Acute promyelocytic leukemia (APL), especially cases of high-risk with complex chromosomes (CK), is rare in individuals infected with human immunodeficiency virus (HIV),...
Acute promyelocytic leukemia (APL), especially cases of high-risk with complex chromosomes (CK), is rare in individuals infected with human immunodeficiency virus (HIV), making the establishment of therapeutic approaches challenging; often the treatment is individualized. This report describes a 49-year-old female patient with HIV who was diagnosed with high-risk APL with a new CK translocation and presents a literature review. At diagnosis, the patient presented with typical t(15;17)(q24;q21) with additional abnormalities, including add(5)(q15), add(5)(q31), add(7)(q11.2) and add(12) (p13). The results of acute myeloid leukemia mutation analysis suggested positivity for calreticulin and lysine methyltransferase 2C genes. The patient received all-trans retinoic acid combined with arsenic trioxide and chemotherapy, with morphologically complete remission after the first cycle of chemotherapy. The present report provided preliminary data for future clinical research.
PubMed: 38694571
DOI: 10.3892/ol.2024.14407 -
Frontiers in Oncology 2024In acute promyelocytic leukemia (APL), hemorrhage, particularly intracranial hemorrhage, is the most common cause of early death. A central venous catheter (CVC) may...
In acute promyelocytic leukemia (APL), hemorrhage, particularly intracranial hemorrhage, is the most common cause of early death. A central venous catheter (CVC) may provide a greater guarantee of safety and comfort to APL patients. However, CVCs have seldom been attempted in APL patients during induction therapy because of concerns about increasing the risk of hemorrhagic complications after this invasive procedure. To evaluate the hemorrhagic risk after CVC placement in APL patients during induction therapy, we retrospectively analyzed 95 newly diagnosed patients with APL from January 2010 to December 2022. Among these patients, 39 patients in the CVC group and 56 patients in the non-CVC group were included. Laboratory and clinical parameters of the two groups were collected and compared. There were no significant differences in median platelet, fibrinogen (Fbg), D-dimer, prothrombin time (PT), white blood count (WBC) and hemoglobin (Hb) between the CVC and non-CVC groups on the first day of the visit (day 0) and the following days (day 4, day 7, day 11, day 14, day 18 and day 21) ( = 0.382, = 0.805, = 0.456, = 0.902, = 0.901 and = 0.097, respectively). The consumption of transfused platelets and Fbg was not significantly different between the CVC group and non-CVC group (5.0 vs. 4.5 units, = 0.34, and 6.8 vs. 6.0, = 0.36, respectively). The last day of platelet and Fbg transfusion was also not significantly different (21 vs. 19, = 0.238 and 7.5 vs. 8.5, = 0.684, respectively). The incidences of total hemorrhagic events and hemorrhagic death were lower in the CVC group than in the non-CVC group (17.9% vs. 37.5%, = 0.04 and 0% vs. 16.1%, = 0.01, respectively). The 30-day survival rate was not significantly different (92.3% vs. 82.1%, respectively, = 0.145) for the CVC group compared with the non-CVC group. Our study suggested that CVCs did not increase the hemorrhagic risk in APL patients during induction therapy and that a CVC should be considered in this type of clinical situation.
PubMed: 38680857
DOI: 10.3389/fonc.2024.1332372 -
International Journal of Molecular... Apr 2024The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is...
The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat's therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects.
Topics: Humans; Apoptosis; Hematologic Neoplasms; Cell Line, Tumor; Cell Survival; Antineoplastic Agents; Cytostatic Agents; Cell Proliferation; Hydroxamic Acids; HL-60 Cells; Matrix Metalloproteinase Inhibitors; Cell Cycle Checkpoints; MAP Kinase Signaling System; Leukemia, Myeloid, Acute; Phenylalanine; Thiophenes
PubMed: 38674139
DOI: 10.3390/ijms25084554 -
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