| 1. |
- Eriksson, Anna, et al.
(författare)
-
Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia
- 2015
-
Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 mu M drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug-drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.
|
|
| 2. |
- Eriksson, Anna, 1977-, et al.
(författare)
-
Somatic Exonic Deletions in RUNX1 Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia
- 2023
-
Ingår i: Clinical Cancer Research. - : American Association for Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 29:15, s. 2826-2834
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: In acute myeloid leukemia (AML), somatic mutations (commonly missense, nonsense, and frameshift indels) in RUNX1 are associated with a dismal clinical outcome. Inherited RUNX1 mutations cause familial platelet disorder. As approximately 5%-10% of germline RUNX1 mutations are large exonic deletions, we hypothesized that such exonic RUNX1 aberrations may also be acquired during the development of AML.Experimental Design: Sixty patients with well-characterized AML were analyzed with multiplex ligation-dependent probe amplification (n = 60), microarray (n = 11), and/or whole-genome sequencing (n = 8).Results: In total, 25 (42% of the cohort) RUNX1-aberrant patients (defined by the presence of classical mutations and/or exonic deletions) were identified. Sixteen patients (27%) carried only exonic deletions, 5 (8%) carried classical mutations, and 4 (7%) carried both exonic deletions and mutations. No significant difference was observed between patients with classical RUNX1 mutations and RUNX1 exonic deletions in median overall survival (OS, 53.1 vs. 38.8 months, respectively, P = 0.63). When applying the European Leukemia Net (ELN) classification including the RUNX1-aberrant group, 20% of the patients initially stratified as intermediate-risk (5% of the whole cohort) were reassigned to the high-risk group, which improved the performance of ELN classification regarding OS between intermediate-and high-risk groups (18.9 vs. 9.6 months, P = 0.09).Conclusions: Somatic RUNX1 exonic deletions constitute a novel recurrent aberration in AML. Our findings have important clinical implications regarding AML classification, risk stratification, and treatment decision. Moreover, they argue in favor of further investigating such genomic aberrations not only in RUNX1 but also in other genes implicated in cancer biology and management.
|
|
| 3. |
- Mou, Tian, et al.
(författare)
-
The transcriptome-wide landscape of molecular subtype-specific mRNA expression profiles in acute myeloid leukemia
- 2021
-
Ingår i: American Journal of Hematology. - : John Wiley & Sons. - 0361-8609 .- 1096-8652. ; 96:5, s. 580-588
-
Tidskriftsartikel (refereegranskat)abstract
- Molecular classification of acute myeloid leukemia (AML) aids prognostic stratification and clinical management. Our aim in this study is to identify transcriptome-wide mRNAs that are specific to each of the molecular subtypes of AML. We analyzed RNA-sequencing data of 955 AML samples from three cohorts, including the BeatAML project, the Cancer Genome Atlas, and a cohort of Swedish patients to provide a comprehensive transcriptome-wide view of subtype-specific mRNA expression. We identified 729 subtype-specific mRNAs, discovered in the BeatAML project and validated in the other two cohorts. Using unique proteomics data, we also validated the presence of subtype-specific mRNAs at the protein level, yielding a rich collection of potential protein-based biomarkers for the AML community. To enable the exploration of subtype-specific mRNA expression by the broader scientific community, we provide an interactive resource to the public.
|
|
| 4. |
- Struyf, Nona, et al.
(författare)
-
Delineating functional and molecular impact of ex vivo sample handling in precision medicine
- 2024
-
Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- Consistent handling of samples is crucial for achieving reproducible molecular and functional testing results in translational research. Here, we used 229 acute myeloid leukemia (AML) patient samples to assess the impact of sample handling on high-throughput functional drug testing, mass spectrometry-based proteomics, and flow cytometry. Our data revealed novel and previously described changes in cell phenotype and drug response dependent on sample biobanking. Specifically, myeloid cells with a CD117 (c-KIT) positive phenotype decreased after biobanking, potentially distorting cell population representations and affecting drugs targeting these cells. Additionally, highly granular AML cell numbers decreased after freezing. Secondly, protein expression levels, as well as sensitivity to drugs targeting cell proliferation, metabolism, tyrosine kinases (e.g., JAK, KIT, FLT3), and BH3 mimetics were notably affected by biobanking. Moreover, drug response profiles of paired fresh and frozen samples showed that freezing samples can lead to systematic errors in drug sensitivity scores. While a high correlation between fresh and frozen for the entire drug library was observed, freezing cells had a considerable impact at an individual level, which could influence outcomes in translational studies. Our study highlights conditions where standardization is needed to improve reproducibility, and where validation of data generated from biobanked cohorts may be particularly important.
|
|
| 5. |
- Trac, Quang Thinh, et al.
(författare)
-
Prediction model for drug response of acute myeloid leukemia patients
- 2023
-
Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Despite some encouraging successes, predicting the therapy response of acute myeloid leukemia (AML) patients remains highly challenging due to tumor heterogeneity. Here we aim to develop and validate MDREAM, a robust ensemble-based prediction model for drug response in AML based on an integration of omics data, including mutations and gene expression, and large-scale drug testing. Briefly, MDREAM is first trained in the BeatAML cohort (n = 278), and then validated in the BeatAML (n = 183) and two external cohorts, including a Swedish AML cohort (n = 45) and a relapsed/refractory acute leukemia cohort (n = 12). The final prediction is based on 122 ensemble models, each corresponding to a drug. A confidence score metric is used to convey the uncertainty of predictions; among predictions with a confidence score >0.75, the validated proportion of good responders is 77%. The Spearman correlations between the predicted and the observed drug response are 0.68 (95% CI: [0.64, 0.68]) in the BeatAML validation set, -0.49 (95% CI: [-0.53, -0.44]) in the Swedish cohort and 0.59 (95% CI: [0.51, 0.67]) in the relapsed/refractory cohort. A web-based implementation of MDREAM is publicly available at https://www.meb.ki.se/shiny/truvu/MDREAM/.
|
|
| 6. |
- Österroos, Albin, et al.
(författare)
-
A risk score based on real-world data to predict early death in acute promyelocytic leukemia
- 2022
-
Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 107:7, s. 1528-1537
-
Tidskriftsartikel (refereegranskat)abstract
- With increasingly effective treatments, early death (ED) has become the predominant reason for therapeutic failure in patients with acute promyelocytic leukemia (APL). To better prevent ED, patients with high-risk of ED must be identified. Our aim was to develop a score that predicts the risk of ED in a real-life setting. We used APL patients in the population based Swedish AML Registry (n=301) and a Portuguese hospital-based registry (n=129) as training and validation cohorts, respectively. The cohorts were comparable with respect to age (median, 54 and 53 years) and ED rate (19.6% and 18.6%). The score was developed by logistic regression analyses, risk-per-quantile assessment and scoring based on ridge regression coefficients from multivariable penalized logistic regression analysis. White blood cell count, platelet count and age were selected by this approach as the most significant variables for predicting ED. The score identified low-, high-and very high-risk patients with ED risks of 4.8%, 20.2% and 50.9% respectively in the training cohort and with 6.7%, 25.0% and 36.0% as corresponding values for the validation cohort. The score identified an increased risk of ED already at sub-normal and normal white blood cell counts and, consequently, it was better at predicting ED risk than the Sanz score (AUROC 0.77 vs. 0.64). In summary, we here present an externally validated and population-based risk score to predict ED risk in a real-world setting, identifying patients with the most urgent need of aggressive ED prevention. The results also suggest that increased vigilance for ED is already necessary at sub-normal/normal white blood cell counts.
|
|
| 7. |
- Österroos, Albin, et al.
(författare)
-
Combination screening in vitro identifies synergistically acting KP372-1 and cytarabine against acute myeloid leukemia
- 2016
-
Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 118, s. 40-49
-
Tidskriftsartikel (refereegranskat)abstract
- Cytogenetic lesions often alter kinase signaling in acute myeloid leukemia (AML) and the addition of kinase inhibitors to the treatment arsenal is of interest. We have screened a kinase inhibitor library and performed combination testing to find promising drug-combinations for synergistic killing of AML cells. Cytotoxicity of 160 compounds in the library InhibitorSelect (TM) 384-Well Protein Kinase Inhibitor I was measured using the fluorometric microculture cytotoxicity assay (FMCA) in three AML cell lines. The 15 most potent substances were evaluated for dose-response. The 6 most cytotoxic compounds underwent combination synergy analysis based on the FMCA readouts after either simultaneous or sequential drug addition in AML cell lines. The 4 combinations showing the highest level of synergy were evaluated in 5 primary AML samples. Synergistic calculations were performed using the combination interaction analysis package COMBIA, written in R, using the Bliss independence model. Based on obtained results, an iterative combination search was performed using the therapeutic algorithmic combinatorial screen (TACS) algorithm. Of 160 substances, cell survival was <= 50% at <0.5 mu M for Cdk/Crk inhibitor, KP372-1, synthetic fascaplysin, herbimycin A, PDGF receptor tyrosine kinase inhibitor IV and reference-drug cytarabine. KP372-1, synthetic fascaplysin or herbimycin A obtained synergy when combined with cytarabine in AML cell lines MV4-11 and HL-60. KP372-1 added 24 h before cytarabine gave similar results in patient cells. The iterative search gave further improved synergy between cytarabine and KP372-1. In conclusion, our in vitro studies suggest that combining KP372-1 and cytarabine is a potent and synergistic drug combination in AML.
|
|
| 8. |
- Österroos, Albin, 1988-
(författare)
-
Improving prognostication and treatment choices for patients with AML
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The treatment landscape of the aggressive haematological malignancy acute myeloid leukaemia (AML) has expanded but the prognosis is still unsatisfactory poor. Here, we aimed at improving prognostication and treatment choices in AML by addressing current clinical obstacles to successful AML treatment.Acute promyelocytic leukaemia (APL) is an AML subset characterised by a high rate of early death (ED). In Paper I, we developed a novel risk score for ED in APL. We identified three risk groups for ED based on regression analyses on first a training cohort from the population-based Swedish AML Registry (n=301) and later an external validation cohort from a hospital-based registry (n=129). The presented risk score included age, platelets and white blood cell (WBC) count. Importantly, already sub-normal to normal WBC counts conferred higher risks of ED.Molecular studies of elderly AML patients are sparse. In Paper II, we focused on patients ≥65 years to investigate the prognostic effect of molecular markers and to propose an algorithm for response to intensive chemotherapy (IC) in this patient group. We combined clinical data with targeted DNA- and RNA-sequencing of 182 patients. Notably, we identified and externally validated three risk categories for complete remission achievement after IC based on mutational status of TP53 and gene expression levels of ZBTB7A and EEPD1.Hypomethylating agents (HMAs) constitute a backbone for AML patients ineligible for IC. There are limited studies on their effectiveness in the real-world setting. In Paper III, we compared the utility of HMAs against IC and palliative care in all AML patients ≥60 years in Sweden (n=3135) during 2008-2018. Propensity score matching in this population-based cohort showed that HMAs are as effective as IC upfront when patient characteristics were balanced. Additionally, predictive factors for overall survival in HMA treated patients were different to IC treated patients.The HMA azacitidine combined with venetoclax is the current frontline option to AML patients unfit for IC. Few studies have addressed how this synergism arises. In Paper IV, we characterised the epigenetic and transcriptomic effects of azacitidine-venetoclax in vitro and elucidated potential survival/resistance mechanisms in AML blasts including the serine synthesis pathway and NTRK signaling. Furthermore, we utilised obtained RNA-seq data and in silico predictions to propose add-ons to azacitidine-venetoclax to further strengthen the synergy.In summary, the research presented herein contributes to improved personalised medicine in AML via real-world data, risk stratification algorithms and insights into potential novel therapeutic approaches.
|
|
| 9. |
- Österroos, Albin, et al.
(författare)
-
Integrated multi-omic profiling of azacitidine-venetoclax in AML reveals additional targetable pathways to improve the treatment
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The combination of venetoclax and azacitidine constitutes the first-line option for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Azacitidine-venetoclax has shown pronounced clinical and preclinical ecacy but the molecular mechanisms causing this synergy remain to be clarified. We applied an integrative multi-omic approach with focus in epigenetics on two AML cell lines to characterize the effects of azacitidine-venetoclax in vitro on chromatin accessibility, DNA methylation and gene expression patterns.We report distinct epigenetic and transcriptomic eects when combining azacitidine and venetoclax as compared to either substance alone. With the application of ATAC-seq, we delineate combination-unique gained pathways including the activation of mRNA splicing and NOTCH-HSF1 signaling but also more widespread heterochromatin compared to azacitidine or venetoclax alone. When assessing methylation status, we observed combination-unique hypermethylation of Rac1- and Rho-associated signaling. We integrate the epigenetic alterations of azacitidine-venetoclax with RNA-seq data and report activation of genes involved in the serine synthesis pathway and NTRK signaling that represent potentially upregulated survival pathways upon azacitidine-venetoclax exposure.We also propose potential synergistic triplet therapies based on in silico drug predictions using condition-wise weighted co-expression networks including inhibitors of proteaseomes, MCL-1 and histone deacetylase. Future studies are needed to investigate whether the inhibition of the mentioned pro-survival pathways or proposed triplets may enhance the effects of azacitidine-venetoclax in AML.
|
|
| 10. |
- Österroos, Albin, et al.
(författare)
-
Integrated transcriptomic and genomic analysis improves prediction of complete remission and survival in elderly patients with acute myeloid leukemia
- 2020
-
Ingår i: Blood Cancer Journal. - : NATURE PUBLISHING GROUP. - 2044-5385. ; 10:6
-
Tidskriftsartikel (refereegranskat)abstract
- Relevant molecular tools for treatment stratification of patients >= 65 years with acute myeloid leukemia (AML) are lacking. We combined clinical data with targeted DNA- and full RNA-sequencing of 182 intensively and palliatively treated patients to predict complete remission (CR) and survival in AML patients >= 65 years. Intensively treated patients withNPM1andIDH2(R172)mutations had longer overall survival (OS), whereas mutatedTP53conferred lower CR rates and shorter OS.FLT3-ITDandTP53mutations predicted worse OS in palliatively treated patients. Gene expression levels most predictive of CR were combined with somatic mutations for an integrated risk stratification that we externally validated using the beatAML cohort. We defined a high-risk group with a CR rate of 20% in patients with mutatedTP53, compared to 97% CR in low-risk patients defined by high expression ofZBTB7AandEEPD1withoutTP53mutations. Patients without these criteria had a CR rate of 54% (intermediate risk). The difference in CR rates translated into significant OS differences that outperformed ELN stratification for OS prediction. The results suggest that an integrated molecular risk stratification can improve prediction of CR and OS and could be used to guide treatment in elderly AML patients.
|
|
| 11. |
|
|
