Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

The DNA Double-Strand Break Response Is Abnormal in Myeloblasts From Patients With Therapy-Related Acute Myeloid Leukemia

ABSTRACT: In order to examine if the upregulation of DNA repair genes on chromosome 8 was associated with the abnormal DSB phenotype observed in trisomy 8 (defined by array CGH or cytogenetics), we compared the mRNA levels of DNA repair genes on chromosome 8 in trisomy 8 t-AML patients versus normal t-AML gammaH2AX responders using gene expression array data. Bone marrow cells taken directly from patients after written informed consent were cryopreserved, RNA extracted, and microarray analysis was performed using Affymetrix U133plus2 chips.

ORGANISM(S): Homo sapiens

SUBMITTER: Matt Walter

PROVIDER: E-GEOD-52478 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia.

Jacoby M A MA De Jesus Pizarro R E RE Shao J J Koboldt D C DC Fulton R S RS Zhou G G Wilson R K RK Walter M J MJ

Leukemia 20131205 6

The complex chromosomal aberrations found in therapy-related acute myeloid leukemia (t-AML) suggest that the DNA double-strand break (DSB) response may be altered. In this study we examined the DNA DSB response of primary bone marrow cells from t-AML patients and performed next-generation sequencing of 37 canonical homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair genes, and a subset of DNA damage response genes using tumor and paired normal DNA obtained from t-AML p ...[more]

PMID: 24304937

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Project description:Human pluripotent stem cells (hPSCs) tend to acquire genomic aberrations in culture, the most common of which is the trisomy of chromosome 12. Interestingly, trisomy 12 is also prevalent in germ cell tumors (GCTs). Here, we aimed to dissect the cellular and molecular implications of trisomy 12 in hPSCs. A genome-wide gene expression analysis revealed that trisomy 12 profoundly affects the global gene expression profile of hPSCs, inducing a transcriptional program very similar to that of CGTs. Direct comparison of the proliferation, replication, differentiation and apoptosis between diploid and aneuploid hPSCs revealed that trisomy 12 significantly increases the proliferation rate of hPSCs. Increased replication largely accounts for the increased proliferation observed, and may explain the selection advantage that trisomy 12 confers to hPSCs. A comparison of the tumors induced by diploid and aneuploid hPSCs further demonstrated that trisomy 12 increases the tumorigenicity of hPSCs, inducing transcriptionally-distinct teratomas, from which pluripotent cells can be recovered. Lastly, a chemical screen of 89 anticancer drugs against diploid and aneuploid hPSCs discovered that trisomy 12 raises the sensitivity of hPSCs to several replication inhibitors, suggesting that the increased proliferation and tumorigenicity of these aberrant cells also makes them more vulnerable, and might potentially be used for their selective elimination from culture. Together, our findings demonstrate the extensive effect of trisomy 12 on the gene expression signature and on the cellular behavior of hPSCs, and highlight the danger posed by this trisomy for the successful use of hPSCs in basic research and in regenerative medicine. Expression data from diploid and aneuoploid human pluripotent stem cells, teratomas derived from them, and pluripotent-like cells recovered from these teratomas total RNA was isolated from undifferentiated human pluripotent stem cells grown under standard human ES conditions, or from teratomas derived from them, or from ES-like cells recovered from these teratomas.

Dataset Information

The DNA Double-Strand Break Response Is Abnormal in Myeloblasts From Patients With Therapy-Related Acute Myeloid Leukemia

Publications

The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia.

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