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Requirement for Lis1 in Normal and Malignant Stem Cell Renewal

dc.contributor.advisor Reya, Tannishtha
dc.contributor.advisor Pendergast, Ann Marie Zimdahl, Bryan Jeffrey 2013-11-14T19:14:22Z 2015-11-04T05:30:05Z 2013
dc.description.abstract <p>Stem cells are defined by their ability to make more stem cells, a property known as self-renewal and their ability to generate cells that enter differentiation. One mechanism by which fate decisions can be effectively controlled in stem cells is through asymmetric division and the correct partitioning and inheritance of cell fate determinants. While hematopoietic stem cells have the capacity to divide through asymmetric division, the molecular machinery that regulates this process is unknown and whether its activity is required in vivo remains unclear. Here we show that Lis1, a dynein-binding protein and regulator of asymmetric division, is critically required for blood development and for hematopoietic stem cell renewal in fetal and adult life. In particular, conditional deletion of Lis1 led to a severe bloodless phenotype and embryonic lethality in vivo. In both fetal and adult mice, loss of Lis1 led to a failure of normal self-renewal, which included impaired colony-forming ability in vitro and defects in long-term reconstitution ability following transplantation. As a possible mechanism, we find that the absence of Lis1 in hematopoietic cells, in part, accelerates differentiation linked to the incorrect inheritance of cell fate determinants. Furthermore, using a live cell imaging strategy, we find that the incorrect inheritance of cell fate determinants observed following the loss of Lis1 is due defects in spindle positioning and orientation. Finally, using two animal models of undifferentiated myeloid leukemia, we show that Lis1 is critical for the aberrant cell growth that occurs in cancer. Deletion of Lis1 both at the early and late stages of myeloid leukemia blocked its propagation in vivo and led to a marked improvement in survival. Together, these data identify Lis1 and the directed control of asymmetric division as key regulators of normal and malignant hematopoietic development.</p>
dc.subject Cellular biology
dc.subject Developmental biology
dc.subject Oncology
dc.subject Asymmetric Cell Division
dc.subject Cancer
dc.subject Hematopoietic Stem Cells
dc.subject Spindle Orientation
dc.title Requirement for Lis1 in Normal and Malignant Stem Cell Renewal
dc.type Dissertation
dc.department Molecular Cancer Biology
duke.embargo.months 24

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