Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse normal lymphoid progenitors and MLL-AF4 leukemic lymphoblasts

ABSTRACT: We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. Experiment Overall Design: Total RNA from normal pro-B, pre-B, immature B and mature B lymphocytes, and from leukemic pre-B cells was isolated and hybridized to Affymetrix expresison microarrays.

ORGANISM(S): Mus musculus

SUBMITTER: Madeleine Lemieux

PROVIDER: E-GEOD-12310 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

H3K79 methylation profiles define murine and human MLL-AF4 leukemias.

Krivtsov Andrei V AV Feng Zhaohui Z Lemieux Madeleine E ME Faber Joerg J Vempati Sridhar S Sinha Amit U AU Xia Xiaobo X Jesneck Jonathan J Bracken Adrian P AP Silverman Lewis B LB Kutok Jeffery L JL Kung Andrew L AL Armstrong Scott A SA

Cancer cell 20081101 5

We created a mouse model wherein conditional expression of an Mll-AF4 fusion oncogene induces B precursor acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Gene expression profile analysis of the ALL cells demonstrated significant overlap with human MLL-rearranged ALL. ChIP-chip analysis demonstrated histone H3 lysine 79 (H3K79) methylation profiles that correlated with Mll-AF4-associated gene expression profiles in murine ALLs and in human MLL-rearranged leukemias. Human MLL-rearrange ...[more]

PMID: 18977325

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Project description:The MLL-AF4 fusion gene is a hallmark genomic aberration in high-risk acute lymphoblastic leukemia in infants. Although it is well-established that MLL-AF4 arises pre-natally during human development, its effects on hematopoietic development in utero remains unexplored. We have created a human-specific in vitro system to study early hemato-endothelial development in MLL-AF4-expressing human embryonic stem cells (hESCs). Differentiation and functional studies as well as clonal analyses and gene expression profiling reveal that expression of MLL-AF4 in hESCs has a phenotypic, functional and gene expression impact. It enhances the specification of hemogenic precursors from hESCs and impairs further hematopoietic commitment of these precursors in favour of the endothelial cell fate. Similar to that reported in cord blood CD34+ hematopoietic stem/progenitor cells (HSPCs), MLL-AF4 expression is not sufficient to transform hESC-derived hematopoietic cells in vitro or in vivo, indicating that additional events may be required to initiate leukemogenesis or that embryonic hematopoiesis is not the appropriate human cellular target for MLL-AF4-mediated leukemogenesis. This work illustrates how hESCs can provide unique insights into human development and further our understanding of how leukemic fusion genes known to arise pre-natally regulate human embryonic hematopoietic specification. MLL is involved in transcriptional regulation and most MLL translocations appear to result in increased expression of Hox genes and hematopoietic genes. We therefore assessed the impact of MLL-AF4 expression on the transcriptome of hESCs. Gene expression profiling performed in MLL-AF4 hESCs revealed that MLL-AF4 preferentially activates transcription. 1826 out of the 3001 genes (61%) expressed were up-regulated in MLL-AF4 hESCs. Human ESC samples were collected during the exponential cell growth phase and stabilized in RNA later. 500 ng of each total RNA sample was labelled with Cy3 using the Quick-Amp Labelling kit and hybridized with the Gene Expression Hybridization kit to a Whole Human Genome Oligo Microarray (Agilent Technologies) following the Manufacturer’s instructions. Each cell line was analyzed as independent duplicates. NEO-expressing (empty lentivector) hESC line was used as the baseline.

Dataset Information

Transcription profiling of mouse normal lymphoid progenitors and MLL-AF4 leukemic lymphoblasts

Publications

H3K79 methylation profiles define murine and human MLL-AF4 leukemias.

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