Pediatric and adult leukemias often exhibit a striking difference in the frequency of associated oncogenes. For example, the TEL/AML1 fusion is exclusively associated with pediatric B-lineage acute lymphoblastic leukemia (B-ALL) and the OTT/MAL and MLL-AF4 are primarily associated with infant leukemias. This is in contrast to the BCR/ABL fusion, which is most frequently found in adults with chronic myelogenous leukemia (CML) and approximately 30% of adult B-lymphoblastic leukemia (B-ALL), but rarely found in pediatric leukemias. The discrepancy in associated oncogenes promotes the hypothesis that the fetal/infant hematopoietic system differs qualitatively from the adult hematopoietic system. Furthermore, our preliminary data indicate differing leukemogenic potential of BCR/ABL in subpopulations of fetal vs adult hematopoietic cells. These specific data provide a compelling argument for further research into the differences between embryonic and adult hematopoiesis and the perturbations caused by expression of oncogenes at precise points during development. ? ? Specific aims for this 5-year proposal outlines specific aims designed to investigate the differences exhibited by fetal hematopoietic stem/progenitor cells and adult bone marrow stem/progenitor cells. ? Understanding the qualitative differences in the properties of fetal liver (FL) vs adult bone marrow (BM) stem and progenitor cells will provide insights about their disparity in leukemogenic potential as well as normal development of the hematopoietic system. ? ? Specific aims include: (1) To compare the effects of oncogene expression in FL stem and progenitor cells when compared to BM equivalents. What are the differences in transformation potential of each population in the presence of oncogene expression? (2) To characterize the differences in transforming potential of highly purified hematopoietic progenitors (HP) from FL or BM. Are there differences in colony forming potential, self-renewal capacity or gene expression between fetal and adult HP? (3) To analyze leukemic potential in other embryonic hematopoietic tissue types. Is fetal liver the only embryonic tissue in which leukemia can arise or can leukemia be induced in purified populations isolated from the aorta-gonad mesonephros region, yolk sac and placenta? ? ? ? ?
| Stone, Jennifer; Thompson, Deborah J; Dos Santos Silva, Isabel et al. (2015) Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures. Cancer Res 75:2457-67 |
