Unknown,Transcriptomics,Genomics,Proteomics

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Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Lars Bullinger

PROVIDER: E-GEOD-23143 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias.

Kvinlaug Brynn T BT Chan Wai-In WI Bullinger Lars L Ramaswami Mukundhan M Sears Christopher C Foster Donna D Lazic Stanley E SE Okabe Rachel R Benner Axel A Lee Benjamin H BH De Silva Inusha I Valk Peter J M PJ Delwel Ruud R Armstrong Scott A SA Döhner Hartmut H Gilliland D Gary DG Huntly Brian J P BJ

Cancer research 20110419 12

Fusion oncogenes in acute myeloid leukemia (AML) promote self-renewal from committed progenitors, thereby linking transformation and self-renewal pathways. Like most cancers, AML is a genetically and biologically heterogeneous disease, but it is unclear whether transformation results from common or overlapping genetic programs acting downstream of multiple mutations or by the engagement of unique genetic programs acting cooperatively downstream of individual mutations. This distinction is import ...[more]

PMID: 21505102

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Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias.

Publications

Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias.

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