A novel differentiation response with combination IDH inhibitor and intensive induction therapy for AML.
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ABSTRACT:
SUBMITTER: Mason EF
PROVIDER: S-EPMC8095142 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
Publications
A novel differentiation response with combination IDH inhibitor and intensive induction therapy for AML.
Mason Emily F EF Pozdnyakova Olga O Roshal Mikhail M Fathi Amir T AT Stein Eytan M EM Ferrell P Brent PB Shaver Aaron C AC Frattini Mark M Wang Hongfang H Hua Lei L Mu Jimmy J Choe Sung S Xu Rengyi R Almon Caroline C Cooper Michael M Stone Richard M RM Hasserjian Robert P RP Savona Michael R MR
Blood advances 20210401 8
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Project description:p53 protein isoform expression has been found to correlate with prognosis and chemotherapy response in acute myeloid leukemia (AML). We aimed to investigate how p53 protein isoforms are modulated during epigenetic differentiation therapy in AML, and if p53 isoform expression could be a potential biomarker for predicting a response to this treatment. p53 full-length (FL), p53β and p53γ protein isoforms were analyzed by 1D and 2D gel immunoblots in AML cell lines, primary AML cells from untreated patients and AML cells from patients before and after treatment with valproic acid (VPA), all-trans retinoic acid (ATRA) and theophylline. Furthermore, global gene expression profiling analysis was performed on samples from the clinical protocol. Correlation analyses were performed between p53 protein isoform expression and in vitro VPA sensitivity and FAB (French-American-British) class in primary AML cells. The results show downregulation of p53β/γ and upregulation of p53FL in AML cell lines treated with VPA, and in some of the patients treated with differentiation therapy. p53FL positively correlated with in vitro VPA sensitivity and the FAB class of AML, while p53β/γ isoforms negatively correlated with the same. Our results indicate that p53 protein isoforms are modulated by and may predict sensitivity to differentiation therapy in AML.
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Project description:Intensive chemotherapy in combination with allogeneic hematopoietic cell transplantation and supportive care can induce long-term remissions in around 50% of acute myeloid leukemia patients eligible for intensive treatment. Several treatment optimization trials helped to refine schedule and dosing of the historic "7 + 3" combination. Together with the addition of novel agents, increased efficacy and tolerability led to improved long-term outcomes. Unsatisfactory outcomes in fit elderly patients and unfavorable genetic subgroups have raised the question of whether less-intensive venetoclax-based approaches may be beneficial as an alternative. Although tempting and worth exploring, this issue will remain controversial until the results of randomized comparisons appear. To date, intensive chemotherapy remains the only evident curative treatment option for long-term disease eradication in a fixed treatment time. With the advent of more novel agents and advances in minimal residual disease (MRD) detection and maintenance approaches, the face of intensive treatment could change in many ways. Several are being explored in clinical trials, such as (1) combinations of more than 1 novel agent with the intensive backbone, (2) head-to-head comparisons of novel agents, (3) replacement or dose reduction of cytotoxic components such as anthracyclines, and (4) MRD-guided escalation and de-escalation strategies. The combination of intensive treatment with individualized tailored innovative strategies will most certainly reduce treatment-related toxicities and increase the chances for long-term remission in the future.
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Project description:INTRODUCTION:Vacuolization is a frequently found morphological feature in acute myeloid leukemia (AML) blasts. Subcellular origin and biological function as well as prognostic impact are currently unknown. The aim of this study was to evaluate whether vacuolization correlates with clinically relevant AML features. MATERIALS & METHODS:Bone marrow smears of patients diagnosed with AML at the University Hospital Frankfurt between January 2011 and August 2013 were analyzed for blast vacuolization and correlated with clinically relevant AML features. Patients undergoing standard induction chemotherapy were further analyzed for molecular and cytogenetic features as well as treatment response and survival. RESULTS:14 of 100 patients diagnosed with AML receiving standard induction chemotherapy had evidence of blast vacuolization. Positivity for vacuolization correlated with a CD15 positive immunophenotype and with a higher incidence of high-risk AML according to the European LeukemiaNet risk stratification. AML patients with blast vacuolization had a poor blast clearance after standard induction chemotherapy and poor survival. DISCUSSION:In conclusion, our findings demonstrate that vacuolization can easily be determined in myeloid leukemia blasts and may be a useful biomarker to predict AML risk groups as well as early treatment response rates and survival.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-22 | GSE151598 | GEO
Project description:The success of all-trans retinoic acid (ATRA) therapy in acute promeylocytic leukemia (APL) has spawned numerous attempts to translate the paradigm of differentiation therapy to non-APL acute myelocytic leukemia (AML). However, the results of clinical trials have been overall disappointing. In this review we discuss the mechanism of retinoic acid signaling and the results of major clinical trials that have attempted to incorporate ATRA into AML regimens. We discuss recent evidence that indicate that the retinoic acid signaling pathway may be dysfunctional in AML. Preliminary studies suggest that targeting the pathways that modify retinoic acid receptor activity may reactivate the dormant retinoic acid-signaling pathway. Such strategies may revive the ability of ATRA to induce myeloid differentiation and apoptosis in non-APL AML.
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Project description:The pharmacodynamics investigations in PXD101-CLN-15 included correlation of response with gene expression (n=13). Gene expression profiling based on 13 patients (4 responders and 9 non- responders) revealed a strong gene expression pattern associated with the response to belinostat. 1905 genes were significant at the p<0.05 level of the univariate test. MLL(p=0.0000769), a gene well known to play a crucial role in leukemogenesis via epigenetic deregulation, was among the top 20 candidates. Of these, differential expression of TP53(p=0.0001817) is also of special interest as histone deacetylase have been shown to modulate p53 transcriptional activity through regulation of p53-DNA binding activity. An additional interesting candidate was CCT5(p=0.000135), chaperonin containing TCP1, subunit 5 (epsilon), a known interactor of HDAC3 and HDAC5 (see http://www.ncbi.nlm.nih.gov/gene/22948) that encodes for a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT). GO (gene ontology) class comparison analysis shows a significant enrichment of gene ontologies including categories associated with epigenetic regulation such as the GO category “histone methyltransferase activity” (comprising e.g. MLL, ASH2L, MEN1, and SUZ12) and “histone deacetylase activity” (comprising e.g. HDAC7, HDAC2, SIRT5, and HDAC2). The gene signature provides insights into the molecular deregulation prone to restoration of epigenetic deregulation, and the respective gene expression pattern also harbors predictive information as demonstrated by the blinded belinostat response prediction based on an in vitro cell line derived predictor.
2014-12-31 | GSE39363 | GEO
Project description:BackgroundMicroarrays used for gene expression studies yield large amounts of data. The processing of such data typically leads to lists of differentially-regulated genes. A common terminal data analysis step is to map pathways of potentially interrelated genes.MethodsWe applied a transcriptomics analysis tool to elucidate the underlying pathways of leukocyte maturation at the genomic level in an established cellular model of leukemia by examining time-course data in two subclones of U-937 cells. Leukemias such as Acute Promyelocytic Leukemia (APL) are characterized by a block in the hematopoietic stem cell maturation program at a point when expansion of clones which should be destined to mature into terminally-differentiated effector cells get locked into endless proliferation with few cells reaching maturation. Treatment with retinoic acid, depending on the precise genomic abnormality, often releases the responsible promyelocytes from this blockade but clinically can yield adverse sequellae in terms of potentially lethal side effects, referred to as retinoic acid syndrome.ResultsBriefly, the list of genes for temporal patterns of expression was pasted into the ABCC GRID Promoter TFSite Comparison Page website tool and the outputs for each pattern were examined for possible coordinated regulation by shared regelems (regulatory elements). We found it informative to use this novel web tool for identifying, on a genomic scale, genes regulated by drug treatment.ConclusionImprovement is needed in understanding the nature of the mutations responsible for controlling the maturation process and how these genes regulate downstream effects if there is to be better targeting of chemical interventions. Expanded implementation of the techniques and results reported here may better direct future efforts to improve treatment for diseases not restricted to APL.
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