Single-cell RNA sequencing of erythroid and megakaryocytic acute myeloid leukemia patient cells
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Homo sapiens
SUBMITTER: Olli Dufva
PROVIDER: E-MTAB-12607 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia.
Kuusanmäki Heikki H Dufva Olli O Vähä-Koskela Markus M Leppä Aino-Maija AM Huuhtanen Jani J Vänttinen Ida I Nygren Petra P Klievink Jay J Bouhlal Jonas J Pölönen Petri P Zhang Qi Q Adnan-Awad Shady S Mancebo-Pérez Cristina C Saad Joseph J Miettinen Juho J Javarappa Komal K KK Aakko Sofia S Ruokoranta Tanja T Eldfors Samuli S Heinäniemi Merja M Theilgaard-Mönch Kim K Wartiovaara-Kautto Ulla U Keränen Mikko M Porkka Kimmo K Konopleva Marina M Wennerberg Krister K Kontro Mika M Heckman Caroline A CA Mustjoki Satu S
Blood 20230301 13
Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the antiapoptotic protein B-cell lymphoma (BCL) ...[more]
Similar Datasets
Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. This data is from the lysate fraction of the secretomes described in PXD001476.
2016-02-03 | PXD003471 | Pride
Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. Herein, we further explored this aspect of apoptosis in AML. Firstly, the intra-individual ex vivo apoptosis-related profiles of normal lymphocytes and AML blasts showed a strong correlation, with expression values far beyond control lymphocytes. Secondly, we demonstrated that apoptosis-resistant primary AML blasts, as opposed to apoptosis-sensitive cells, were able to up-regulate BCL-2 expression in sensitive AML blasts in contact cultures (p=0.0067 and p=1.0 respectively). Using proteomics we further set out to identify novel proteins possibly engaged in apoptosis regulation. Proteomics analysis revealed that major functional protein clusters upregulated in secretomes of apoptosis-resistant AML, were presumably engaged in global gene regulation including mRNA splicing, protein translation and chromatin remodeling.
2016-02-03 | PXD001476 | Pride
Project description:In acute myeloid leukemia (AML) non-random clonal chromosome aberrations are detectable in ~55% of adults with AML. Translocation t(8;21)(q22;q22) resulting in the 5'RUNX1/3'RUNX1T1 fusion gene occurs in ~8% of acute myeloid leukemia (AML) cases. Also, insertions ins(8;21) and ins(21;8) have been described that show a broad heterogeneity at the molecular level with inserted fragment sizes ranging from 2.4 to 44 Mb. Microarray-based comparative genomic hybridization (arrayCGH) in 49 intermediate-risk AML and RT-PCR-based screening in 532 AML cases allowed the detection of ins(21;8)/ins(8;21) in three cases; arrayCGH and subsequent RT-PCR revealed an ~0.5 Mb sized inserted fragment generating the 5'RUNX1/3'RUNX1T1 fusion gene in one case with a submicroscopic ins(21;8)(q22;q22q22) whereas the other two cases were identified by banding analysis and RT-PCR, respectively. Gene expression profiling (GEP) and a detailed review of the literature highlighted similar biological features of AML cases with ins(21;8)/ins(8;21) and t(8;21)(q22;q22). Our study demonstrates the potential of high-resolution array-based analysis and GEP and provides further evidence that AML with insertions generating the 5'RUNX1/3'RUNX1T1 fusion not only biologically resemble the t(8;21)(q22;q22) AML subgroup, but might also share their prognostically favorable clinical behavior. Thus, similar treatment options should be considered in these patients. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract.
2010-10-26 | E-GEOD-24384 | biostudies-arrayexpress
Project description:Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation, and to evaluate the utility of a FLT3 signature for prognostication. The dataset comprises gene-expression profiles of 137 normal karyotype acute myeloid leukemia (NK-AML) specimens carried out using Stanford cDNA microarrays, to accompany the study of L Bullinger et al. For each array, Channel 2 represents Cy5-labeled NK-AML RNA, and Channel 1 Cy3-labeled universal reference RNA. Keywords: Logical Set DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases. Supervised analysis was applied to build a gene expression-based predictor of FLT3-ITD mutation status. The predictor was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases.
2008-02-27 | E-GEOD-8043 | biostudies-arrayexpress
Project description:In this report we demonstrate that the ability to alter self-renewal in vitro and in vivo is a more generalized property of leukemia-associated oncogenes. We further demonstrate that disparate leukemia-associated oncogenes initiate early common and overlapping transformation and self-renewal gene expression programs to mediate these effects. Furthermore, elements of these programs can be detected in established leukemia stem cells from an animal model and across a large cohort of patients with differing acute myeloid leukemia (AML) subtypes, where they strongly predict for disease biology. Finally, individual genes from the programs are demonstrated to partially phenocopy the leukemia-associated oncogenes and themselves alter self-renewal in committed murine progenitors and generate AML when expressed in murine bone marrow. A total of 253 RNA samples derived from adult AML patients were provided by the German Austrian AML Study Group (AMLSG) [AMLSG trials AML HD98A (ClinicalTrials.gov Identifier: NCT00146120), and AML HD98B (Schlenk et al., 2009)]. Conventional cytogenetic banding, and FLT3, CEBPA and NPM1 mutational analysis were performed as previously described (Schlenk et al., N Engl J Med 2008). Detailed clinical, cytogenetic and molecular cytogenetic information are also provided in Table S3 along with the publication. Following enrichment, all samples contained at least 80% leukemic cells. Gene expression profiling (GEP) was performed as previously described (Bullinger et al., N Engl J Med 2004). Separate filtering and batch centering were performed for the group of 253 Samples (relative to GSE16432). Filtered data presented as a supplementary file at the foot of this record.
2011-06-27 | E-GEOD-23143 | biostudies-arrayexpress
Project description:PURPOSE: To evaluate frequency, biological features and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML). PATIENTS AND METHODS: Diagnostic samples from 945 patients (18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n=269) microarray gene expression analysis was performed. RESULTS: Fifty-nine RUNX1 mutations were identified in 53 of 945 (5.6%) cases, predominantly in exons 3 (n=11), 4 (n=10) and 8 (n=23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46/640, 7.2%; cytogenetically normal, 34/538, 6.3%), they were less frequent in adverse-risk cytogenetics (5/109, 4.6%), and absent in core-binding-factor AML (0/77) and acute promyelocytic leukemia (0/61); RUNX1 mutations were associated with MLL-partial tandem duplications (p=0.0007) and IDH1/IDH2 mutations (p=0.03), inversely correlated with NPM1 (p<0.0001) and in trend with CEBPA (p=0.10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3) or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, p=0.047, for RUNX1-mutated and wildtype patients, respectively), as well as inferior event-free survival (EFS; p<0.0001), relapse-free survival (RFS, p=0.022), and overall survival (p=0.051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (p=0.007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (p<0.0001). CONCLUSION: AML with RUNX1 mutations exhibit distinct biological properties and are associated with resistance to therapy and inferior outcome. A total of 269 RNA samples derived from adult AML patients were provided by the German Austrian AML Study Group (AMLSG) [AMLSG trial AML HD98A (ClinicalTrials.gov Identifier: NCT00146120)]. Conventional cytogenetic banding, and FLT3, CEBPA and NPM1 mutational analysis were performed as previously described (Schlenk et al., N Engl J Med 2008). Detailed clinical, cytogenetic and molecular cytogenetic information are also provided in the supplementary information. Following enrichment, all samples contained at least 80% leukemic cells. Gene expression profiling (GEP) was performed as previously described (Bullinger et al., N Engl J Med 2004).
2010-12-31 | E-GEOD-23312 | biostudies-arrayexpress
Project description:RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML). Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc.
2010-07-11 | E-GEOD-16432 | biostudies-arrayexpress
Project description:Background: MicroRNAs are regulators of gene expression, mainly functioning by decreasing mRNA levels of their multiple targets. Deregulated microRNA expression has been shown for acute myeloid leukemia, a disease also characterized by altered gene expression associated with distinct genomic aberrations such as nucleophosmin (NPM1) mutations. To further illuminate the role of deregulated microRNA and gene expression in cytogenetically normal acute myeloid leukemia with NPM1 mutation, we performed an integrative analysis of microRNA and mRNA expression data sets. Design and Methods: Both microRNA and gene expression profiles were measured in a cohort of 43 adult acute myeloid leukemia patient samples (n=42 cytogenetically normal, n=1 del7q; median age 46 years [range 23-60]) of known NPM1 mutation status (n=23 mutated, n=20 wild-type) and data integratively analyzed. Putative microRNA-mRNA interactions were validated by quantitative RT-PCR, Western Blot and luciferase reporter assays. For selected microRNAs, sensitivity of microRNA-overexpressing cells to cytarabine treatment was tested by FACS viability and cell proliferation assays. Results: Our integrative approach of analyzing both microRNA and gene expression profiles in parallel resulted in a refined list of putative target genes affected by NPM1 mutation-associated microRNA deregulation. Of 177 putative microRNA - target mRNA interactions, we could identify and validate 77 novel candidates with known or potential implication in leukemogenesis, such as IRF2-miR-20a, KIT-miR-20a and MN1-miR-15a. Furthermore, our data showed that deregulated expression of tumor suppressor microRNAs such as miR-29a and miR-30c might contribute to the sensitivity to cytarabine, which is observed in NPM1-mutated acute myeloid leukemia. Conclusions: Overall, our observations highlight that integrative data analysis approaches can improve insights into leukemia biology, and lead to the identification of novel microRNA - target gene interactions of potential relevance for acute myeloid leukemia treatment. MicroRNA and gene expression profiles were measured in a cohort of 43 adult (42 cytogenetically normal and 1 del7q) acute myeloid leukemia patient samples of known NPM1 mutation status (n=23 mutated, n=20 wild-type). This submission represents the mRNA expression component of the study. The miRNA expression data will be deposited as supplementary information along with the accompanying manuscript.
2011-09-11 | E-GEOD-31644 | biostudies-arrayexpress
Project description:Purpose: The tet oncogene family member 2 (TET2) gene was recently identified mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored frequency, gene expression pattern, and clinical impact of TET2mut in a large cohort of AML patients, in the context of other AML-associated aberrations. Patients and Methods: Samples from 783 younger adult AML patients were analyzed for the presence of TET2mut (coding exons 3-11), and results were correlated with data from molecular genetic analyses, gene expression profiling, and clinical outcome. Results: In total, 66 TET2mut were found in 60 (60/783; 7.6%) patients, including missense (n=37), frameshift (n=16), and nonsense (n=13) mutations, which with one exception were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (p<0.001). TET2mut were characterized by only a weak gene expression pattern, which nevertheless reflected TET2mut-associated biology. TET2mut did not impact response to induction therapy and clinical outcome; combining patients exhibiting TET2mut and/or IDHmut revealed shorter overall survival (p=0.03), although this association was not independent from known risk factors. Conclusion: TET2mut were identified in 7.6% of younger adult AML patients and did not impact response to therapy and survival. Mutations were mutually exclusive with IDHmut, thereby supporting recent data on a common mechanism of action, which might obscure the impact of TET2mut if compared against all other AML cases. We performed a supervised class comparison analysis comparing 31 TET-mutated AML cases (TET2 mut) vs. 302 TET2-wildtype AML cases (TET wt) to see if a specific gene expression pattern associated with the presence of the identified TET2 mutations could be determined. No technical replicates were performed.
2011-12-31 | E-GEOD-32246 | biostudies-arrayexpress
Project description:Purpose: This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML). Conclusions: NF1 null states are present in 7/95=7% of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mTOR-directed therapeutics. Experimental design: We analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for recurrent genomic microdeletions using ultra-high density Affymetrix SNP 6.0 array-based genomic profiling. 006, 096 and 136 normal Samples have been excluded from study.
2010-12-02 | E-GEOD-21107 | biostudies-arrayexpress