Immune responses and therapeutic challenges in paediatric patients with new-onset acute myeloid leukaemia and concomitant COVID-19.
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ABSTRACT:
SUBMITTER: Patel PA
PROVIDER: S-EPMC8239563 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic.
| S-EPMC8468645 | biostudies-literature
Project description:The management of acute myeloid leukaemia (AML) in India remains a challenge. In a two-year prospective study at our centre there were 380 newly diagnosed AML (excluding acute promyelocytic leukaemia, AML-M3) patients. The median age of newly diagnosed patients was 40 years (range: 1-79; 12.3% were ≤ 15 years, 16.3% were ≥ 60 years old) and there were 244 (64.2%) males. The median duration of symptoms prior to first presentation at our hospital was 4 weeks (range: 1-52). The median distance from home to hospital was 580 km (range: 6-3200 km). 109 (29%) opted for standard of care and were admitted for induction chemotherapy. Of the 271 that did not take treatment the major reason was lack of financial resources in 219 (81%). There were 27 (24.7%) inductions deaths and of these, 12 (44.5%) were due to multidrug-resistant gram-negative bacilli and 12 (44.5%) showed evidence of a fungal infection. The overall survival at 1 year was 70.4% ± 10.7%, 55.6% ± 6.8% and 42.4% ± 15.6% in patients aged ≤ 15 years, 15 - 60 years and ≥ 60 years, respectively. In conclusion, the biggest constraint is the cost of treatment and the absence of a health security net to treat all patients with this diagnosis.
| S-EPMC4864448 | biostudies-literature
Project description:Acute myeloid leukaemia (AML) is a clinically and molecularly heterogeneous disease characterised by uncontrolled proliferation, block in differentiation and acquired self-renewal of hematopoietic stem and myeloid progenitor cells. This results in the clonal expansion of myeloid blasts within the bone marrow and peripheral blood. The incidence of AML increases with age, and in childhood, AML accounts for 20% of all leukaemias. Whilst there are many clinical and biological similarities between paediatric and adult AML with continuum across the age range, many characteristics of AML are associated with age of disease onset. These include chromosomal aberrations, gene mutations and differentiation lineage. Following chemotherapy, AML cells that survive and result in disease relapse exist in an altered chemoresistant state. Molecular profiling currently represents a powerful avenue of experimentation to study AML cells from adults and children pre- and postchemotherapy as a means of identifying prognostic biomarkers and targetable molecular vulnerabilities that may be age-specific. This review highlights recent advances in our knowledge of the molecular profiles with a focus on transcriptomes and metabolomes, leukaemia stem cells and chemoresistant cells in adult and paediatric AML and focus on areas that hold promise for future therapies.
| S-EPMC8410545 | biostudies-literature
Project description:Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Although the overall survival of children with ALL is now more than 90%, leukaemia remains one of the leading causes of death from disease. In developed countries, the overall survival of patients with ALL has increased to more than 80%; however, those children cured from ALL still show a significant risk of short- and long-term complications as a consequence of their treatment. Accordingly, there is a need not only to develop new methods of diagnosis and prognosis but also to provide patients with less toxic therapies. MicroRNAs (miRNAs) are small ribonucleic acids (RNA), usually without coding potential, that regulate gene expression by directing their target messenger RNAs (mRNAs) for degradation or translational suppression. In paediatric ALL, several miRNAs have been observed to be overexpressed or underexpressed in patient cohorts compared to healthy individuals, while numerous studies have identified specific miRNAs that can be used as biomarkers to diagnose ALL, classify it into subgroups, and predict prognosis. Likewise, a variety of miRNAs identify as candidate targets for treatment, although there are numerous obstacles to overcome before their clinical use in patients. Here, we summarise the roles played by different miRNAs in childhood leukaemia, focussing primarily on their use as diagnostic tools and potential therapeutic targets, as well as a role in predicting treatment outcome. Finally, we discuss the potential roles of miRNA in immunotherapy and the novel contributions made by gut miRNAs to regulation of the host microbiome.
| S-EPMC6815594 | biostudies-literature
Project description:FUS-ERG is a chimeric gene with a poor prognosis, found in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). It remains unclear whether DNA hypomethylating agents, including azacitidine (Aza), are effective in FUS-ERG-harbouring AML and how FUS-ERG induces chemoresistance. Stable Ba/F3 transfectants with FUS-ERG were repeatedly exposed to Aza for 7 days of treatment and at 21-day intervals to investigate Aza sensitivity. Stable FUS-ERG transfectants acquired resistance acquired resistance after three courses of Aza exposure. RNA sequencing (RNA-seq) was performed when Aza susceptibility began to change; genes with altered expression or transcript variants were identified. Molecular signatures of these genes were analysed using gene ontology. RNA-seq analyses identified 74 upregulated and 320 downregulated genes involved in cell motility, cytokine production, and kinase activity. Additionally, 1321 genes with altered transcript variants were identified, revealing their involvement in chromatin organisation. In a clinical case of AML with FUS-ERG, we compared whole-genome alterations between the initial MDS diagnosis and AML recurrence after Aza treatment. Genes with non-synonymous or near mutations in transcription regulatory areas (TRAs), additionally detected in AML recurrence, were collated with the gene list from RNA-seq to identify genes involved in acquiring Aza resistance in the presence of FUS-ERG. Whole-genome sequencing of clinical specimens identified 29 genes with non-synonymous mutations, including BCOR, and 48 genes located within 20 kb of 54 TRA mutations in AML recurrence. These genes were involved in chromatin organisation and included NCOR2 as an overlapping gene with RNA-seq data. Transcription regulators involved in mutated TRAs were skewed and included RCOR1 in AML recurrence. We tested the efficacy of BH3 mimetics, including venetoclax and S63845, in primary Aza-resistant AML cells treated with FUS-ERG. Primary FUS-ERG-harbouring AML cells acquiring Aza resistance affected the myeloid cell leukaemia-1 (MCL1) inhibitor S63845 but not while using venetoclax, despite no mutations in BCL2. FUS-ERG promoted Aza resistance after several treatments. The disturbance of chromatin organisation might induce this by co-repressors, including BCOR, NCOR2, and RCOR1. MCL1 inhibition could partially overcome Aza resistance in FUS-ERG-harbouring AML cells.
| S-EPMC10475016 | biostudies-literature
Project description:This study was to investigate the circular RNA (circRNA) expression profile and the potential circRNAs as biomarkers and therapeutic targets for acute myeloid leukaemia (AML). CircRNA expression profile in bone marrow mononuclear cells from 5 AML patients and 5 healthy donor controls (HCs) was evaluated by microarray. Then, 10 candidate circRNAs (top 5 upregulated and top 5 downregulated) from microarray were validated by RT-qPCR in 130 AML patients and 50 HCs. Finally, the effects of circRNA annexin A2 (circ-ANXA2) knockdown on cell proliferation, apoptosis, chemosensitivity to cytarabine, daunorbicin and potential target microRNAs were assessed in THP-1 and KG-1 cells. By microarray, 173 upregulated and 181 downregulated circRNAs were found in AML patients than HCs, and these circRNAs were found in AML patients compared with HCs, and these circRNAs were implicated in AML-related pathways such as ErbB and EGFR pathways. By RT-qPCR, 9 of 10 candidate circRNAs (including circ-RPS6KB1, circ-CSMD2, circ-PTK2, circ-ANXA2, circ-PWP2, circ-RBM5, circ-ZZEF1, circ-GSK3B and circ-FOXP1) were dysregulated in AML patients compared with HCs. Circ-ANXA2 correlated with higher disease risk, poor risk stratification, lower complete remission level, shorter event-free survival and overall survival in AML. In cellular experiments, circ-ANXA2 was upregulated in AML cell lines, and its knockdown suppressed proliferation, enhanced apoptosis of THP-1 and KG-1 cells and increased their chemosensitivity to cytarabine and daunorbicin. Additionally, circ-ANXA2 knockdown promoted microRNA (miR)-23a-5p and miR-503-3p expression in THP-1 and KG-1 cells. In conclusion, our findings provide a macroscopic view of the circRNA expression profile in AML, and demonstrate that circ-ANXA2 may be a potential biomarker and therapeutic target for AML.
| S-EPMC7270033 | biostudies-literature
Project description: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.
| S-EPMC3468705 | biostudies-literature
Project description:Combined bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) exert unexpected antileukaemic activities against acute myeloid leukaemia (AML) and these activities are associated with the generation of reactive oxygen species (ROS) within the tumor cells. Although the generation of ROS by these drugs is supported by preceding studies including our own, the interrelationship between the cellular effects of the drugs and ROS generation is not well understood. Here we report the use of NMR metabolomic profiling to further study the effect of BEZ and MPA on three AML cell lines and to shed light on the underlying mechanism of action. For this we focused on drug effects induced during the initial 24 hours of treatment prior to the onset of overt cellular responses and examined these in the context of basal differences in metabolic profiles between the cell lines. Despite their ultimately profound cellular effects, the early changes in metabolic profiles engendered by these drugs were less pronounced than the constitutive metabolic differences between cell types. Nonetheless, drug treatments engendered common metabolic changes, most markedly in the response to the combination of BEZ and MPA. These responses included changes to TCA cycle intermediates consistent with recently identified chemical actions of ROS. Notable amongst these was the conversion of alpha-ketoglutarate to succinate which was recapitulated by the treatment of cell extracts with exogenous hydrogen peroxide. These findings indicate that the actions of combined BEZ and MPA against AML cells are indeed mediated downstream of the generation of ROS rather than some hitherto unsuspected mechanism. Moreover, our findings demonstrate that metabolite profiles represent highly sensitive markers for genomic differences between cells and their responses to external stimuli. This opens new perspectives to use metabolic profiling as a tool to study the rational redeployment of drugs in new disease settings.
| S-EPMC2621336 | biostudies-literature
Project description:Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases. Thus, additional genetic or molecular mechanisms must cause primary chemoresistance in paediatric and adult AML.
| S-EPMC5177472 | biostudies-literature
Project description:Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.
| S-EPMC3328300 | biostudies-literature