Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

MDS and DNA repair defects in Crebbp+/- mice

ABSTRACT: Myelodysplastic syndrome (MDS) is considered a disease of hematopoietic stem cell (HSC) origin. To begin to unravel the molecular mechanisms underlying the deregulation of HSCs in MDS, we performed comparative gene expression profiling on Crebbp+/- and wild type HSCs. We chose to isolate HSCs from the fetal liver (FLHSC) because at this stage there were no differences in cell number between Crebbp+/- and wild type fetal livers, suggesting no overt hematopoietic differences. Thus, any change in gene expression found in Crebbp+/- FLHSCs is likely to reflect the initially compromised genetic program of HSC regulation, as opposed to that of Crebbp+/- HSCs in adult bone marrow, where secondary changes in gene expression may also occur as compensatory mechanisms for a compromised or failing hematopoietic system. We used day 14.5 post coitus FLHSC (Sca-1+,Lin-,AA4.1+,c-Kit++) from wild type (wt) and Crebbp heterozygous (ht) embryos to examine changes in gene expression before overt myelodysplastic disease manifestation. Total RNA from wt and Crebbp+/- FLHSCs was isolated, PCR-amplified using the Ovation RNA amplification system and hybridized to Affymetrix Mouse 430 2.0 expression microarrays.

ORGANISM(S): Mus musculus

SUBMITTER: Madeleine Lemieux

PROVIDER: E-GEOD-18061 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Mice heterozygous for CREB binding protein are hypersensitive to γ-radiation and invariably develop myelodysplastic/myeloproliferative neoplasm.

Zimmer Stephanie N SN Lemieux Madeleine E ME Karia Bijal P BP Day Claudia C Zhou Ting T Zhou Qing Q Kung Andrew L AL Suresh Uthra U Chen Yidong Y Kinney Marsha C MC Bishop Alexander J R AJ Rebel Vivienne I VI

Experimental hematology 20111220 4

Myelodysplastic syndrome is a complex family of preleukemic diseases in which hematopoietic stem cell defects lead to abnormal differentiation in one or more blood lineages. Disease progression is associated with increasing genomic instability and a large proportion of patients go on to develop acute myeloid leukemia. Primarily a disease of the elderly, it can also develop after chemotherapy. We have previously reported that CREB binding protein (Crebbp) heterozygous mice have an increased incid ...[more]

PMID: 22198154

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Project description:Clinical GATA2 deficiency syndromes arise from germline haploinsufficiency inducing mutations in GATA2, resulting in immunodeficiency that evolves to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). How GATA2 haploinsufficiency disrupts the function and transcriptional network of hematopoietic stem/progenitors (HSCs/HSPCs) to facilitate the shift from immunodeficiency sequalae to pre-leukemia is poorly characterised. Using a conditional mouse model harboring a single allele deletion of Gata2 when HSCs emerge in utero, we identify pervasive defects in HSPC differentiation from young adult Gata2 haploinsufficient mice during B-cell maturation, early erythroid specification, megakaryocyte maturation to platelets and inflammatory cell generation. Gata2 haploinsufficiency abolishes HSC self-renewal and multi-lineage differentiation capacity following transplantation. These alterations closely associate with deregulated DNA damage responses and inflammatory signalling conveyed from Gata2 haploinsufficient HSCs. We also identify functional interplay between Gata2 and Asxl1, a driver of DNA damage and inflammation and, notably, a recurrent secondary mutation found in GATA2 haploinsufficiency disease progression to MDS/AML. shRNA mediated knockdown of Asxl1 in Gata2 haploinsufficient HSPCs led to a differentiation block in committed progenitor formation beyond that in Gata2 haploinsufficient HSPCs. By analysis of HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice, we discover hyperproliferation of double haploinsufficent HSCs, which are also functionally compromised in transplantation compared to their single haploinsufficient counterparts. Through both Gata2/Asxl1 dependent and unique transcriptional programs, HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice fortify deregulated DNA damage responses and inflammatory signalling in HSCs initiated in Gata2 haploinsufficient mice and establish a broad pre-leukemic program. Our data reveal how Gata2 haploinsufficiency initially drives deregulation of HSC genome integrity and suggest the mechanisms of how secondary mutations like ASXL1 take advantage of HSC genomic instability to nurture a pre-leukemic state in GATA2 haploinsufficiency syndromes.

Dataset Information

MDS and DNA repair defects in Crebbp+/- mice

Publications

Mice heterozygous for CREB binding protein are hypersensitive to γ-radiation and invariably develop myelodysplastic/myeloproliferative neoplasm.

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