Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcriptional profiling of Cebpa knock-in mutant LSK hematopoietic stem cells

ABSTRACT: Gene expression of LSK (lin-Sca-Kit+) hematopoietic stem cells from wild type mice was compared with LSK from Cebpa knock-in mutant mice (K/K, K/L, and L/L mutants). Fetal liver cells for each genotype were competitively transplanted into irradiant recipients. Donor-derived LSK cells were isolated by FACS sorting of recipient bone marrow. 3 biological replicates of each were generated and expression profiles were determined by hybridization to Affymetrix Moe430_2 arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Claus Nerlov

PROVIDER: E-TABM-695 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.

Bereshchenko Oxana O Mancini Elena E Moore Susan S Bilbao Daniel D Månsson Robert R Luc Sidinh S Grover Amit A Jacobsen Sten Eirik W SE Bryder David D Nerlov Claus C

Cancer cell 20091101 5

We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBPalpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBPalp ...[more]

PMID: 19878871

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Project description:C/EBPalpha is a transcription factor critically involved in myeloid development and indispensable for formation of granulocytes. To track the cellular fate of stem and progenitor (LSK) cells, which express C/EBPalpha, we developed a mouse model expressing Cre recombinase from the Cebpa promoter and an inducible EYFP allele. We show that Cebpa/EYFP+ cells represent a significant subset of LSK cells, which predominantly give rise to myeloid cells in steady state hematopoiesis. C/EBPalpha induced a robust myeloid gene expression signature and downregulated E2A-induced regulators of early lymphoid development. In addition, Cebpa/EYFP+ cells comprise a fraction of early thymic progenitors (ETP) with robust myeloid potential. However, Cebpa/EYFP+ LSK and ETP cells retained the ability to develop into erythroid and T-lymphoid lineages, respectively. These findings support an instructive, but argue against a lineage restrictive role of C/EBPalpha in multipotent hematopoietic and thymic progenitors. We performed global gene expression profiling of double-sorted Cebpa/EYFP+ and Cebpa/EYFP- LSK cells of pooled Cebpa Cre/wt R26 EYFP reporter mice to identify differentially regulated genes in Cebpa+ versus Cebpa- LSK cells. RNA was isolated from three biological replicates of Cebpa/EYFP+ LSK cells and two biological replicates of Cebpa/EYFP- LSK cells. To determine if the identified genes were truly dependent on Cebpa expression, we also performed global gene expression profilling of Cebpa/EYFP+ and Cebpa/EYFP- fetal liver LSK cells of Cebpa Cre/fl R26 EYFP mice. Induction of Cebpa/Cre expression in these mice leads to Cre-mediated recombination of the floxed wt Cebpa allele resulting in a complete Cebpa knock-out. In this case, RNA was isolated from two biological replicates of either Cebpa/EYFP+ and Cebpa/EYFP- LSK cells. In addition, we included one biological replicate of Cebpa/EYFP+ and Cebpa/EYFP- fetal liver LSK cells of Cebpa Cre/wt R26 EYFP mice to determine the correlation of differentially regulated genes in bone marrow and fetal liver LSK cells.

Dataset Information

Transcriptional profiling of Cebpa knock-in mutant LSK hematopoietic stem cells

Publications

Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML.

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