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1.  Temozolomide-mediated DNA methylation in human myeloid precursor cells:differential involvement of intrinsic and extrinsic apoptotic pathways 
Purpose
An understanding of how hematopoietic cells respond to therapy that causes myelosuppression will help develop approaches to prevent this potentially life-threatening toxicity. The goal of this study was to determine how human myeloid precursor cells (MP) respond to temozolomide (TMZ)-induced DNA damage.
Experimental Design
We developed an ex vivo primary human MP cells model system to investigate the involvement of cell-death pathways using a known myelosuppressive regimen of O6-benzylguanine (6BG) and TMZ.
Results
Exposure to 6BG/TMZ led to increases in p53, p21, ╬│-H2AX, and mitochondrial DNA damage. Increases in mitochondrial membrane depolarization correlated with increased caspase-9 and caspase-3 activities following 6BG/TMZ treatment. These events correlated with decreases in activated AKT, downregulation of the DNA repair protein O6methylguanine-DNA methyltransferase (MGMT), and increased cell death. During MP cell expansion, FAS/CD95/APO1(FAS) expression increased over time and was present on ~100% of the cells following exposure to 6BG/TMZ. While c-flipshort, an endogenous inhibitor of FAS-mediated signaling, was decreased in 6BG/TMZ-treated versus control, 6BG-, or TMZ alone-treated cells, there were no changes in caspase-8 activity. Additionally, there were no changes in the extent of cell death in MP cells exposed to 6BG/TMZ in the presence of neutralizing or agonistic anti-FAS antibodies, indicating that FAS-mediated signaling was not operative.
Conclusions
In human MP cells, 6BG/TMZ-initiated apoptosis occurred by intrinsic, mitochondrial-mediated and not extrinsic, FAS-mediated apoptosis. Human MP cells represent a clinically relevant model system for gaining insight into how hematopoietic cells respond to chemotherapeutics and offer an approach for selecting effective chemotherapeutic regimens with limited hematopoietic toxicity.
doi:10.1158/1078-0432.CCR-12-2671
PMCID: PMC3711223  PMID: 23536437
2.  The genetic landscape of mutations in Burkitt lymphoma 
Nature genetics  2012;44(12):1321-1325.
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
doi:10.1038/ng.2468
PMCID: PMC3674561  PMID: 23143597

Results 1-3 (3)