Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Integrating resistance functions to predict response to induction chemotherapy in de novo acute myeloid leukemia

ABSTRACT: This study explored resistance functions and their interactions in de novo AML treated with the "7 + 3" induction regimen. We analyzed RNA-sequencing profiles of whole bone marrow samples from 52 de novo AML patients who completed the "7 + 3" regimen and stratified patients into CR (n = 35) and non-CR (n = 17) groups. A systematic gene set analysis revealed significant associations between chemoresistance and mTOR (P < .001), myc (P < .001), mitochondrial oxidative phosphorylation (P < .001), and stemness (P = .002). These functions were independent with regard to gene contents and activity scores. An integration of these four functions showed a prediction of chemoresistance (area under the receiver operating characteristic curve = 0.815) superior to that of each function alone. Moreover, our proposed seven-gene scoring system significantly correlated with the four-function model (r = .97; P < .001) to predict chemoresistance to the "7 + 3" regimen. On multivariate analysis, a seven-gene score of ≥-0.027 (hazard ratio: 11.18; 95% confidence interval: 2.06-60.65; P = .005) was an independent risk factor for induction failure. In summary, Myc, OXPHOS, mTOR, and stemness were responsive for chemoresistance in AML. Treatments other than the "7 + 3" regimen need to be considered for de novo AML patients predicted to be refractory to the "7 + 3" regimen.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103424 | GEO | 2020/08/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Chemoresistance in acute myeloid leukemia: a single-cell RNA sequencing approach

Project description:Introduction Our previous study demonstrated that myc, mitochondrial oxidative phosphorylation, mTOR, and stemness were independently responsible for chemoresistance in AML. The current study aimed to further identify the potential mechanisms of chemoresistance of the “7+3” induction in AML using a single-cell RNA sequencing (scRNA-seq) approach. Methods Thirteen untreated de novo AML patients were enrolled and stratified into the complete remission (CR) (n = 8) and the non-CR (n = 5) groups. We used scRNA-seq to analyze the genetic profiles of 28950 AML cells from these 13 patients. A previously published bulk RNA-seq dataset validated our results. Results Chemoresistant AML cells had more premature accumulation in early hematopoiesis. The hematopoietic stem cell-like cells from the non-CR group expressed more leukemic stem cell markers (CD9, CD82, IL3RA and, IL1RAP) than those from the CR group. Besides, chemoresistant progenitor cells had impaired myeloid differentiation due to early hematopoiesis arrest. Importantly, the AML cells analyzed by the scRNA-seq and bulk RNA-seq honored comparable myeloid lineage cell fraction, which internally validated our results. Using the TCGA database, our analysis demonstrated that AML patients with a higher expression of chemoresistant genetic markers (IL3RA and IL1RAP had a worse overall survival (p < 0.01 for IL3RA; p < 0.05 for IL1RAP).

2023-03-01 | GSE198681 | GEO

Lin28A/CENPE promoting the proliferation and chemo-resistance of acute myeloid leukemia

Project description:Peripheral blood samples of 3 refractory/relapsed AML patients (R/R-AML, relapsed/refractory AML patients who failed to achieve complete remission/CR after 2 courses of induction chemotherapy), 3 refractory secondary AML patients (S-AML, MDS or MPN derived AML patients did not reach CR after 2 rounds of induction chemotherapy), 4 de novo AML patients (AML, CR after standard “3+7” induction chemotherapy), and 3 healthy controls (HC) were collected. Nanodrop was applied to quantify the total RNA samples. Illumina kits were used to prepare the RNA-seq library.

2021-09-10 | GSE183817 | GEO

c-Myc facilitates prediction of "7+3" induction failure in de novo acute myeloid leukaemia with high-risk cytogenetics

Project description:This study aimed to identify whether c-Myc could facilitate prediction of "7+3" induction failure in de novo acute myeloid leukaemia (AML) with high-risk cytogenetics. Seventy-five untreated de novo AML patients who completed the "7+3" induction therapy were enrolled (24 patients from a prospective cohort; 51 patients from a retrospective cohort) and stratified into complete remission (CR) and non-CR groups. Myc-associated molecular signature between the CR and non-CR groups in the prospective cohort was compared after gene set enrichment analysis. c-Myc protein expression was assessed via immunohistochemical staining. A high c-Myc-immunopositivity was defined when ≥ 40% of bone marrow myeloblasts were c-Myc (+). Our results revealed that AML patients who did not achieve CR by the "7+3" induction therapy had a higher Myc gene expression than those that achieved CR (p=0.047). Myc gene expression was positively correlated with c-Myc protein expression (p=0.014). Although the non-CR group did not have more c-Myc protein expression compared to that in the CR group (p=0.151), combination of high c-Myc-immunopositivity and high-risk cytogenetics increased the probability of "7+3" induction failure compared to that in high-risk cytogenetics alone. Induction strategies other than “7+3” might be a solution for de novo patients with high c-Myc-immunopositivity and high-risk cytogenetics.

2021-04-01 | GSE164894 | GEO

Gene Expression Signature Predicts Relapse in Adult Patients with Cytogenetically Normal Acute Myeloid Leukemia

Project description:Although approximately 80% of adult patients with cytogenetically normal acute myeloid leukemia (CN-AML) achieve a complete remission (CR), over half of them relapse. Better identification of patients who are likely to relapse can help inform clinical decisions. We performed RNA sequencing on pretreatment samples from 268 adults with de novo CN-AML younger than 60 years who achieved a CR after induction treatment with standard “7+3” chemotherapy. After filtering for genes whose expressions were associated with gene mutations known to impact on outcome (i.e., CEBPA, NPM1, and FLT3-internal tandem duplication [FLT3-ITD]), we identified a 10-gene signature strongly predictive of patient relapse (area under the curve [AUC]=0.81). The signature consisted of seven coding genes: GAS6, PSD3, PLCB4, DEXI, JMY, NRP1, C10orf55, and three long non-coding RNAs. In multivariable analysis, the 10-gene signature was strongly associated with relapse (P<.001), after adjustment for the FLT3-ITD, CEBPA and NPM1 mutational status. Validation of the expression signature in an independent patient set from The Cancer Genome Atlas showed the signature’s strong predictive value with AUC=0.78. Implementation of the 10-gene signature into clinical prognostic stratification could be useful for identifying patients likely to relapse.

2021-03-16 | GSE165430 | GEO

Implications of the miR-10 family in chemotherapy response of NPM1 mutated AML

Project description:Nucleophosmin mutated AML (NPM1mut-AML) patients have a high rate of complete remission (CR) to induction chemotherapy. However, the mechanisms responsible for such effects are unknown. Since miR-10 family members are expressed at high levels in NPM1mut-AML, we evaluated whether these microRNAs could predict chemotherapy response in AML. We found that high baseline miR-10 family expression in 54 untreated cytogenetically heterogeneous AML patients was associated with achieving CR. However, when we included NPM1 mutation status in the multivariable model, there was a significant interaction effect between miR-10a-5p expression and NPM1 mutation status. Similar results were observed when using a second cohort of 183 cytogenetically normal older (ageM-bM-^IM-%60 years) AML patients. Loss and gain of function experiments using miR-10a-5p in cell lines and primary blasts did not demonstrate any effect in apoptosis or cell proliferation at baseline or after chemotherapy. These data support a bystander role for the miR-10 family in NPM1mut-AML. Pretreatment miRNA expression was analyzed in 54 de novo adult AML patients obtained from the MD Anderson Cancer Center Leukemia Tissue Bank (LTB) using the Ohio State University (OSU) miRNA microarray (ver.3).

2014-05-01 | E-GEOD-55519 | biostudies-arrayexpress

The BCL-2 Inhibitor Venetoclax in Combination with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Acute Myeloid Leukemia Patients

Project description:The manuscript summarizes clinical and laboratory-based evaluation of 33 AML patients treated with a novel drug combination, venetoclax and azacytidine. Our findings indicate that this regimen is exceptionally promising for the treatment of de novo AML patients. The improvement in outcomes in comparison to conventional therapy is quite remarkable. The manuscript explores the mechanistic basis for the clinical outcomes, testing the hypothesis that venetoclax and azacytidine effectively target leukemia stem cells (LSCs) in vivo. Our findings indicate the regimen is highly active towards the LSC population. Specifically, we describe a mechanism that suppresses the activity of electron transport complex II, resulting in inhibition of oxidative phosphorylation.

2018-09-01 | GSE116567 | GEO

SIRT3 SUMOylation confers AML chemoresistance via down-regulation of HES1 dependent fatty acid oxidation

Project description:SIRT3 deacetylase is a critical mitochondrial regulator for mitochondrial metabolism reprogramming and ROS production, and is involved in the regulation of chemoresistance in AML. SIRT3 is a SUMOylated protein, with de-SUMOylation by SENP1, resulted in enhancement of its deacetylase activity. However, the molecular mechanism of de-SUMOylation mediated SIRT3 activation, which may lead to reinforced AML chemoresistance, remains poorly understood. In the current study, we demonstrated that SIRT3 SUMOylation was attenuated by cytarabine, and de-SUMOylation prevented SIRT3 from proteasome degradation. SIRT3 de-SUMOylation was capable of reprogramming mitochondrial biogenesis, and subsequently inhibited mitochondrial ROS production. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation, among which the transcription factor HES1, a downstream substrates of Notch1 signaling pathway, was significantly downregulated by SIRT3K288R, the de-SUMOylated and constitutively active mutant of SIRT3. HES1-dependent FAO was inhibited by SIRT3 de-SUMOylation. Moreover, cytarabine synergized with the SENP1 inhibitor momodrin-Ic to eradicate AML blasts in vitro and in xenografts mice models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in regulating chemoresistance in AML via HES1-dependent FAO, which may provide a rationale for SIRT3 SUMOylation-targeted intervention to improve the chemotherapies in AML.

2022-08-17 | GSE179617 | GEO

Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

Project description:Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. We developed an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We found that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses. Mechanistically, DNMTi suppressed the outgrowth of a pre-determined set of chemoresistant AML clones with stemness properties, instead favoring the expansion of rarer and unfit chemosensitive clones. Importantly, we confirmed the capacity of DNMTi combination to suppress stemness-dependent chemoresistance development in both xenotransplantation models and primary AML patient samples. Together, these results support the potential of DNMTi combination treatment to circumvent the development of chemorefractory AML relapses.

2019-07-19 | GSE134506 | GEO

Transcription profiling of human hematopoietic stem cell like fractions from individuals with the M2 subtype of acute myeloid leukemia

Project description:AC133+ cells were prepared from bone marrow of individuals with acute myeloid leukemia (AML) with M2 subtype. Comparison was made between de novo AML and MDS-associated AML.

2003-10-09 | E-MEXP-25 | biostudies-arrayexpress

Genome-wide Genotyping of Acute Myeloid Leukemia with Translocation t(9;11)(p22;q23) Reveals Novel Recurrent Genomic Alterations

Project description:To identify cooperating lesions in de novo and therapy-related acute myeloid leukemia (t-AML) with translocation t(9;11)(p22;q23) we performed high-resolution SNP-array profiling on 40 leukemia samples [de novo: n=22; t-AML: n=16; unknown: n=2]. A mean of 1.73 copy number alterations (CNAs)/case were identified with no differences between de novo and t-AML cases. We identified a novel minimally deleted region (MDR) at 7q36.1-q36.2 partly overlapping with a MDR previously identified in core-binding factor AML; MLL3 was the only gene affected in both regions. In addition, a recurrent gain was found at 13q21.33-q22.1 harboring the potential oncogene KLF5. Sequence/expression analysis of selected candidate genes revealed deregulated EVI1 at high frequency (50%). Copy-neutral loss-of-heterozygosity (CN-LOH) was absent in the paired cohort Further analysis of the candidate genes might provide novel insights into the pathogenesis of t(9;11) AML SNP genotyping was performed on 40 de novo and therapy-related MLL-MLLT3-rearranged acute myeloid leukemia samples; Germline control DNA from remission bone marrow or peripheral blood was available for paired analysis in 15 patients. Data were processed using reference alignment, dChipSNP and circular binary segmentation.

2014-05-22 | E-GEOD-46745 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data