Assessment of a new genomic classification system in acute myeloid leukemia with a normal karyotype

Ahn, Jae‐Sook; Kim, Hyeoung-Joon; Kim, Yeo-Kyeoung; Lee, Seung-Shin; Ahn, Seo-Yeon; Jung, Sung‐Hoon; Yang, Deok‐Hwan; Lee, Je‐Jung; Park, Hee Jeong; Lee, Jayeon; Choi, Seung Hyun; Jung, Chul Won; Jang, Jun‐Ho; Kim, Sang-Yong; Moon, Joon Ho; Sohn, Sang Kyun; Lee, Yoo Jin; Won, Jong-Ho; Kim, Sung-Hyun; Zhang, Zhaolei; Kim, TaeHyung; Kim, Dennis Dong Hwan

doi:10.18632/oncotarget.23575

Cited by 17 publications

(14 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aberrant myeloid homeostasis in Acute myeloid leukemia (AML) leads to an increase in myeloid progenitor cells at the expense of mature blood cells 1. 10-15% of AML patients harbor mutations in the CEBPA gene2–4, which encodes the transcription factor (TF) CCAAT/enhancer binding protein alpha (C/EBPα). C/EBPα controls self-renewal properties of hematopoietic stem and progenitor cells (HSPCs) as well as critical steps of myeloid differentiation 5–7.…”

Section: Introductionmentioning

confidence: 99%

CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

et al. 2019

View full text Add to dashboard Cite

The gene encoding the transcription factor C/EBPα is mutated in 10-15% of acute myeloid leukemia (AML) patients. N-terminal CEBPA mutations cause ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is incompletely understood. Here, we demonstrate that the MLL1 histone-methyltransferase complex represents a critical actionable vulnerability in CEBPA -mutated AML. Oncogenic C/EBPα p30 and MLL1 show global co-localization on chromatin and p30 exhibits robust physical interaction with the MLL1 complex. CRISPR/Cas9-mediated mutagenesis of MLL1 results in proliferation arrest and myeloid differentiation in C/EBPα p30-expressing cells. In line, CEBPA -mutated hematopoietic progenitor cells are hypersensitive to pharmacological targeting of the MLL1 complex. Inhibitor treatment impairs proliferation and restores myeloid differentiation potential in mouse and human AML cells with CEBPA mutations. Finally, we identify the transcription factor GATA2 as a direct critical target of the p30-MLL1 interaction. Altogether, we show that C/EBPα p30 requires the MLL1 complex to regulate oncogenic gene expression and that CEBPA -mutated AML is hypersensitive to perturbation of the MLL1 complex. These findings identify the MLL1 complex as a potential therapeutic target in AML with CEBPA mutations.

show abstract

Section: Introductionmentioning

confidence: 99%

CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Indeed, mutated or de‐regulated master transcription factors are regularly identified as oncogenic drivers in leukemia . Mutations in the CEBPA gene are found in 10–15% of de novo acute myeloid leukemia (AML) cases, predominantly in patients with normal karyotype acute myeloid leukemia (NK‐AML) . The mutations are not equally distributed across the CEBPA locus but cluster in two hotspots in different regions of the gene ( Figure ).…”

Section: Introduction: C/ebpα Isoforms and Their Functionsmentioning

confidence: 99%

Gain‐of‐Function Effects of N‐Terminal CEBPA Mutations in Acute Myeloid Leukemia

2019

View full text Add to dashboard Cite

Mutations in theCEBPA gene are present in 10-15% of acute myeloid leukemia (AML) patients. The most frequent type of mutations leads to the expression of an N-terminally truncated variant of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBP ), termed p30. While initial reports proposed that p30 represents a dominant-negative version of the wild-type C/EBP protein, other studies show that p30 retains the capacity to actively regulate gene expression. Recent global transcriptomic and epigenomic analyses have advanced the understanding of the distinct roles of the p30 isoform in leukemogenesis. This review outlines direct and indirect effects of the C/EBP p30 variant on oncogenic transformation of hematopoietic progenitor cells and discusses how studies of N-terminal CEBPA mutations in AML can be extrapolated to identify novel gain-of-function features in oncoproteins that arise from recurrent truncating mutations in transcription factors.

show abstract

“…Individuals with AML have previously been partitioned into 11 genomic subgroups, based on patterns of comutation. 27 , 28 In this case study, we assessed the prevalence of these clinical subgroups using somatic mutations from 182 patients with AML, sequenced by The Cancer Genome Atlas and obtained from the Genomic Data Commons ( gdc.cancer.gov ). Genomic subgroups that were defined by inversions, translocations, and gene fusion events were omitted from this analysis because these variant types are not currently supported by OpenCRAVAT:…”

Section: Resultsmentioning

confidence: 99%

Integrated Informatics Analysis of Cancer-Related Variants

Pagel

Kim

Moad

et al. 2020

JCO Clinical Cancer Informatics

View full text Add to dashboard Cite

PURPOSE The modern researcher is confronted with hundreds of published methods to interpret genetic variants. There are databases of genes and variants, phenotype-genotype relationships, algorithms that score and rank genes, and in silico variant effect prediction tools. Because variant prioritization is a multifactorial problem, a welcome development in the field has been the emergence of decision support frameworks, which make it easier to integrate multiple resources in an interactive environment. Current decision support frameworks are typically limited by closed proprietary architectures, access to a restricted set of tools, lack of customizability, Web dependencies that expose protected data, or limited scalability. METHODS We present the Open Custom Ranked Analysis of Variants Toolkit 1 (OpenCRAVAT) a new open-source, scalable decision support system for variant and gene prioritization. We have designed the resource catalog to be open and modular to maximize community and developer involvement, and as a result, the catalog is being actively developed and growing every month. Resources made available via the store are well suited for analysis of cancer, as well as Mendelian and complex diseases. RESULTS OpenCRAVAT offers both command-line utility and dynamic graphical user interface, allowing users to install with a single command, easily download tools from an extensive resource catalog, create customized pipelines, and explore results in a richly detailed viewing environment. We present several case studies to illustrate the design of custom workflows to prioritize genes and variants. CONCLUSION OpenCRAVAT is distinguished from similar tools by its capabilities to access and integrate an unprecedented amount of diverse data resources and computational prediction methods, which span germline, somatic, common, rare, coding, and noncoding variants.

show abstract

Assessment of a new genomic classification system in acute myeloid leukemia with a normal karyotype

Cited by 17 publications

References 18 publications

CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

Gain‐of‐Function Effects of N‐Terminal CEBPA Mutations in Acute Myeloid Leukemia

Integrated Informatics Analysis of Cancer-Related Variants

Contact Info

Product

Resources

About