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Modeling and Analysis of Acute Leukemia using Human Hematopoietic Stem and Progenitor Cells

Lin, Shan
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1481032144780412

Abstract Details

2016, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
For decades, elegant mouse models have yielded important insights into the complex biology of acute leukemia development. However, species differences between human and mouse could have significant influences on biological and translational applications. Therefore, human primary hematopoietic cells and xenograft mouse models have become important research tools in the field. In this report, we briefly review the methodologies that use human primary hematopoietic cells to model acute leukemia and examine the effects of leukemic oncogenes. The advantages and limitations of the human model system compared to syngeneic mouse models are discussed. The species-related complexity in human disease modeling is highlighted in the study establishing a faithful model of proB-ALL caused by MLL-AF4, the fusion product of the t(4;11). MLL-AF4 proB-ALL has poor prognosis, the lack of an accurate model hampers the study of disease pathobiology and therapeutic testing. We find human AF4 cDNA inhibits retroviral production and efficient transduction, this limitation can be overcome by fusing MLL with murine Af4, highly conserved with human AF4. Whereas MLL-Af4-transduced murine cells induce only AML, transduced human CD34+ cells produce proB-ALL faithful to t(4;11) disease, fully recapitulating the immunophenotypic and molecular aspects of the disease. We find that MLL-fusion leukemia shows genetic heterogeneity driven by differential DNA binding of the fusion proteins. We report lineage plasticity as a new mechanism of resistance to CD19-directed therapy in t(4;11) patients that exemplifies the clinic relevance of our model. This model can provide unique insight for targeting t(4;11) ALL. In addition, by using a pre-leukemia model of AML1-ETO, the fusion protein generated by t(8;21) and associated with AML, we identify FOXO1 as an essential self-renewal factor in this disease. FOXO1 is consistently upregulated in t(8;21) AML and functions as a critical oncogenic mediator rather than a tumor suppressor. Expression of FOXO1 in human CD34+ cells promotes a pre-leukemic state, partially phenocopying the cellular and transcriptional effects of AML1-ETO expression. These functions are specific to FOXO1 and are not elicited by FOXO3, and the DNA binding ability of FOXO1 is required. AML1-ETO and FOXO1 co-occupy the majority of their binding sites, whereby FOXO1 binds to multiple crucial self-renewal genes and is necessary for their activation. In agreement with this observation, loss of FOXO1 inhibits the long-term proliferation and clonogenicity of AML1-ETO cells. Thus, increased FOXO1 represents a new mechanism for acquiring aberrant self-renewal by pre-leukemia stem cells and provides a novel target for therapeutic intervention. This study also serves as an example to demonstrate the usefulness and capacity of the human model system to dissect critical targets and pathways for acute leukemia development.
James Mulloy, Ph.D. (Committee Chair)
Geraldine Guasch, Ph.D. (Committee Member)
Ashish Kumar, M.D. Ph.D. (Committee Member)
Daniel Starczynowski, Ph.D. (Committee Member)
Yi Zheng, Ph.D. (Committee Member)
115 p.
Biology
acute leukemia; MLL-AF4; AML1-ETO; FOXO1; human

Recommended Citations

Citations

  • Lin, S. (2016). Modeling and Analysis of Acute Leukemia using Human Hematopoietic Stem and Progenitor Cells [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1481032144780412

    APA Style (7th edition)

  • Lin, Shan. Modeling and Analysis of Acute Leukemia using Human Hematopoietic Stem and Progenitor Cells. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1481032144780412.

    MLA Style (8th edition)

  • Lin, Shan. "Modeling and Analysis of Acute Leukemia using Human Hematopoietic Stem and Progenitor Cells." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1481032144780412

    Chicago Manual of Style (17th edition)

ucin1481032144780412
568
© 2016, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.