Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

doi:10.1056/nejmx130028

Cited by 5 publications

(5 citation statements)

References 34 publications

(41 reference statements)

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“…Population 1: TCGA LAML. The TCGA-LAML [ 21 ] data were downloaded from cBioPortal (downloaded on 26 January 2020) or using the R package TCGAbiolinks that directly perform queries in the GDCquery (accessed on 29 November 2020). The TCGA-LAML includes mRNA expressions of 173 AML patients (of which survival data are available for 161 patients).…”

Section: Methodsmentioning

confidence: 99%

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Projection of Expression Profiles to Transcription Factor Activity Space Provides Added Information

Bornshten

Danilenko

Rubin

2022

Genes

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Acute myeloid leukemia (AML) is an aggressive type of leukemia, characterized by the accumulation of highly proliferative blasts with a disrupted myeloid differentiation program. Current treatments are ineffective for most patients, partly due to the genetic heterogeneity of AML. This is driven by genetically distinct leukemia stem cells, resulting in relapse even after most of the tumor cells are destroyed. Thus, personalized treatment approaches addressing cellular heterogeneity are urgently required. Reconstruction of Transcriptional regulatory Networks (RTN) is a tool for inferring transcriptional activity in patients with various diseases. In this study, we applied this method to transcriptome profiles of AML patients to test if it provided additional information for the interpretation of transcriptome data. We showed that when RTN results were added to RNA-seq results, superior clusters were formed, which were more homogenous and allowed the better separation of patients with low and high survival rates. We concluded that the external knowledge used for RTN analysis improved the ability of unsupervised machine learning to find meaningful patterns in the data.

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Section: Methodsmentioning

confidence: 99%

“…The data downloaded from TCGAbiollinks included only 145 known patients (of which only 134 had survival information). A complete description of this population is provided elsewhere [ 21 ]. Briefly, the characteristics of the patients used in this study is given in Table 1 below.…”

Section: Methodsmentioning

confidence: 99%

Projection of Expression Profiles to Transcription Factor Activity Space Provides Added Information

Bornshten

Danilenko

Rubin

2022

Genes

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“…Acute myeloid leukemia (AML) arises from genetic abnormalities in hematopoietic stem or progenitor cells (HSPC), responsible for uncontrolled growth and accumulation of neoplastic blasts in the bone marrow (BM). AML is an aggressive, clinically and biologically heterogeneous disease, in which a large number of recurrently mutated genes have been identified [1]. A stepwise acquisition of more than one alteration is required for leukemia development although it is not always clear how single mutations contribute to leukemogenesis [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in Isocitrate Dehydrogenase (IDH) 1 and 2 were originally identified in glioma [4,5], AML, myeloproliferative neoplasm, myelodysplastic syndrome patients [6][7][8] and in other solid tumors [9,10]. In AML approximately 20% of patients carry these mutations, especially in the setting of normal karyotype [1,11]. IDH1 mutations occur thereabout in 7%-10% of patients, while 10%-15% are IDH2 mutated and their frequency increases with age [6,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

The Leukemic IDH1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPC): Experimental Evidences and a Review of the Literature

Pierangeli,

Donnini,

Ciaurro

et al. 2024

Preprint

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How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we studied isocitrate dehydrogenases (IDH) genes mutations in the human model of HSPC and provide a review of the literature on this topic. IDH1/2 mutations occur in ~20% of AML, are recognized among the mutations earliest acquired during leukemogenesis, and are target of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on the HSPC we expressed by lentiviral transduction either IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by the specific inhibitors, confirming it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed over time a progressive and marked improvement of their fitness in terms of CFU ability and propensity to differentiate, attaining clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

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“…Pathogenic variants within IDH1 or IDH2 occur in approximately 20% of AML (5). These mutations include R132 (in IDH1) and R140/R172 (in IDH2), which lead to the production of the oncometabolite 2-hydroxyglutarate and are targeted with selective oral inhibitors (6,7).…”

Section: Introductionmentioning

confidence: 99%

Impact of IDH1 c.315C>T SNP on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study

et al. 2022

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Acute myeloid leukemia (AML) is the common type of acute leukemia in adults. Definitive prognostic significance of variants of unknown significance lacks for many commonly mutated genes, including the isocitrate dehydrogenase 1 (IDH1) synonymous single nucleotide polymorphism (SNP) variant c.315C>T. In this retrospective cohort study of 248 AML patients at the University of Maryland Greenebaum Comprehensive Cancer Center, we show that the IDH1 c.315C>T SNP, previously reported to be associated with poor prognosis by other studies with conflicting data, does not confer worse prognosis, with a median overall survival (OS) of 17.1 months compared to 15.1 months for patients without this SNP (P=0.57). The lack of negative effect on prognosis by IDH1 SNP c.315C>T is consistent with the absence of amino acid alteration (p.Gly105Gly).

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Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

Abstract: and et al, ,"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

Cited by 5 publications

References 34 publications

Projection of Expression Profiles to Transcription Factor Activity Space Provides Added Information

Projection of Expression Profiles to Transcription Factor Activity Space Provides Added Information

The Leukemic IDH1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPC): Experimental Evidences and a Review of the Literature

Impact of IDH1 c.315C>T SNP on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study

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