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Type I interferon signaling in malignant blasts contributes to treatment efficacy in AML patients

ABSTRACT: While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor (TLR3)-dependent mechanism that is not influenced by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms driven by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling has independent prognostic value on relapse-free survival and overall survival in cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225138 | GEO | 2023/03/24

REPOSITORIES: GEO

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Oncogenic RAS primes primary acute myeloid leukemia blasts for differentiation

Project description:RAS mutations are frequently found among AML patients, generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We previously showed that treatment of AML patients with high-dose cytarabine (HDAC) is preferentially beneficial for those with an oncogenic RAS mutation. By applying a murine AML model, we could ascribe this effect to a RAS-driven, p53-dependent induction of differentiation. Here, we sought to confirm the correlation between RAS status and differentiation of blasts obtained from AML patients. The expression signature of primary AML blasts expressing oncogenic RAS where compared to blasts with wtRAS. Blasts where obtained from peripheral blood or bone marrow samples from patients with CBFbeta-MYH11 translocations and with or without an additional NRAS point mutation. As a reference, the Kasumi-1 acute myeloid leukemia cell line was used.

2015-11-20 | E-MTAB-2090 | biostudies-arrayexpress

Global gene expression profile of primary human leukemic blasts

Project description:The goal of this study is to define the global gene expression profile of primary leukemic blasts from patients with different forms of myeloid leukemia and different FAB subtypes. Here we report the global gene expression profile of 2 patients with AML FAB M5, 2 patients with AML FAB M7, 3 patients with Down syndrome AML FAB M7 and 3 patients with Down syndrome transient leukemia.

2009-12-29 | GSE19681 | GEO

Transcription profiling of human hematopoietic cells from 38 healthy donors and leukemic blasts from 26 AML patients

Project description:Acute myeloid leukemia (AML) is one of the most common and deadly forms of hematopoietic malignancies. We hypothesized that microarray studies could identify previously unrecognized expression changes that only occur only in AML blasts. We were particularly interested in those genes with increased expression in AML, believing that these genes may be potential therapeutic targets. Experiment Overall Design: We compared gene expression profiles between normal hematopoietic cells from 38 healthy donors and leukemic blasts from 26 AML patients. Normal hematopoietic samples included CD34+ selected cells (N = 18), unselected bone marrows (N = 10), and unselected peripheral bloods (N = 10).

2008-06-16 | E-GEOD-9476 | biostudies-arrayexpress

Expression data from human AML blasts and healthy CD34+ bone marrow cells

Project description:Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the bone marrow (BM) stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Iradubicin (standard AML chemotherapy) by interfering with the BM stroma-mediated chemoresistance. We report that lenalidomide and pomalidomide have cytotoxic effects on neither AML cells nor BM-MSCs, but they increase the immunosuppressive/immunomodulatory properties of BM-MSCs. When combined with AraC and Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide highly mobilizes AML cells, but not healthy CD34+ cells, to peripheral blood (PB) likely through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize AML blasts to PB through downregulation of CXCR4 but do not improve AraC/Idarubicin activity in a preclinical model of AML.

2019-05-17 | GSE106748 | GEO

Methylation data of serially sorted primary AML patient blasts prior and after treatment with the DNMT inhibitor decitabine (DAC)

Project description:The therapeutic effect of DNA-hypomethylating agents (HMAs) in AML/MDS is discussed to be via its effects on aberrant gene silencing by reactivation (e.g. through promoter demethylation). While this has been broadly studied in cell line models, only very few studies have addressed the global effects of HMAs in primary blasts serially isolated from AML patients (pts) undergoing HMA treatment (Claus et al., Leuk. Res. 2013, Klco et al., Blood 2013, Welch et al., N. Engl. J. Med. 2016). We therefore conducted prospective serial methylome and transcriptome analyses on AML blasts from pts of the DECIDER trial (NCT00867672), hypothesizing that both random and non-random effects of the HMA may be observed in vivo.

2023-04-24 | GSE175758 | GEO

Gene expression data of serially sorted primary AML patient blasts prior and after treatment with the DNMT inhibitor decitabine (DAC)

2022-08-31 | GSE171053 | GEO

Transcription profiling of human acute myeloid leukemia samples from subjects younger than 60 years old

Project description:The pretreatment karyotype of leukemic blasts is currently the key determinant in therapy decision-making in acute myeloid leukemia (AML). However, approximately fifty percent of AML patients, often carrying a normal karyotype, are currently unclassifiable based these established methods. Gene expression profiling has proven to be valuable for risk stratification of AML. The gene expression profiles of AML samples of two independent cohorts (n=247 and n=214) were determined using Affymetrix U133Plus2.0 GeneChips: all Samples (starting with 'amlrrays 2') below 4000 are in the training cohort; all Samples higher than 4000 are in the validation cohort. Data analyses were carried out to discover and predict prognostically relevant subtypes in AML (<60 years) based on their gene expression signatures. Statistical analyses were performed to determine the prognostic significance of cases of AML with specific molecular signatures. Unsupervised cluster analyses of the gene expression signatures of both independent cohorts of AML patients confirmed that chromosomal lesions and mutations, often resulting in aberrant transcription factors, induce discriminatory patterns of gene expression. In contrast, however, mutations in signalling molecules do not establish strong molecular signatures. Consequently, prognostically important subtypes, which express mutated trancription factors were predicted with high accuracy using minimal sets of genes. We identified several novel clusters, some consisting of patients with normal karyotypes. Gene expression profiling allows classification of AML subtypes characterized by the expression of abnormal transcription factors, however, prediction of clinically relevant mutations affecting signalling molecules is impossible and thus still requires addition molecular methods. Experiment Overall Design: 461 blood or bone marrow samples of acute myeloid leukemia patients were hybridized to Affymetrix HG-U133 plus 2 GeneChips.

2008-04-05 | E-GEOD-6891 | biostudies-arrayexpress

Molecular response of AML blasts to Aza-treatment.

Project description:Azacytidine (Aza) treatment is effective in some patients with acute myeloid leukemia (AML). Clinical observations suggest that DNMT3A-mutant patients represent a subgroup of AML patients that responds particularly well to Aza-treatment. Data coming from a mouse model support this finding and we have already generated molecular data suggesting a molecular pathway involved in Aza-response in DNMT3A-mutant AML patients. We now aim to validate these findings in primary AML-blasts. To this end, we have FACS-sorted blasts from patients with AML prior to and under Aza-treatment and plan to correlate pre-treatment as well as on-treatment methylomes to clinical Aza-response.

| EGAS00001004825 | EGA

Defective NK cells in AML patients at diagnosis are associated with blast transcriptional signatures of immune evasion

Project description:Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which may be sensitive to the natural killer (NK) cell anti-tumor response. However, NK cells are frequently defective in AML. Here, we found in an exploratory cohort (n = 46) that NK-cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK-cell profile, including reduced expression of some activating NK receptors (e.g. DNAM-1, NKp46 and NKG2D) and decreased IFN-g production, had a significantly higher risk of relapse (P = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g. IL15, IFNGR1, IFNGR2, CXCR4), antigen processing (e.g. HLA-DRA, HLA-DRB1, CD74) and adhesion molecule pathways (e.g. PVR, ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK-cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications. 5 normal AML cells were compared with 8 NK deficient AML cells.

2015-07-24 | E-GEOD-50928 | biostudies-arrayexpress

662 adult acute myeloid leukemia (AML) cases characterized on the Affymetrix Human Genome U133 Plus 2.0 Microarray

Project description:The pretreatment karyotype of leukemic blasts is currently the key determinant in therapy decision-making in acute myeloid leukemia (AML). However, approximately fifty percent of AML patients, often carrying a normal karyotype, are currently unclassifiable based these established methods. Gene expression profiling has proven to be valuable for risk stratification of AML. This is a repository of 662 adult AML cases characterized on gene expression microarrays and used for different studies investigating the mechanisms underlying leukemogenesis. Bone marrow aspirates or peripheral blood samples of three independent representative cohorts of de novo AML patients, comprising 277, 256 and 129 cases respectively, were collected at diagnosis. Gene expression profiling was performed on 662 adult AML patients who have been treated according to Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON/SAKK) AML-04, -04A, -29, -32, -42, -42A, -43 and -92 protocols (available at http://www.hovon.nl). All patients provided written informed consent in accordance with the Declaration of Helsinki, and the study was approved by all participating institutional review boards. Blast cell purification and RNA isolation were performed as previously described (Valk et al., Prognostically Useful Gene-Expression Profiles in Acute Myeloid Leukemia, New England Journal of Medicine, 2004).

2016-06-23 | E-MTAB-3444 | biostudies-arrayexpress

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