Dr. Milner's research interests are:
1) Stem Cells
4) The role of Notch signaling during hematopoietic differentiation of embryonic stem cells.
Research in her laboratory is guided by two fundamental questions: what are the molecular mechanisms responsible for the generation of diverse cell types from pluripotent stem cells, and how do aberrations in normal developmental pathways contribute to pediatric malignancies?
As a model system, they are using embryonic stem (ES) cells to evaluate the role of Notch signaling in hematopoietic cell fate decisions. Signaling through the Notch pathway is critical for appropriate cell fate specification during a variety of developmental processes. The unique capacity of Notch to function both as a cell-surface receptor and transcriptional regulator provides a mechanism by which cell-cell interactions can directly influence gene expression in neighboring cells. This direct communication between cells has two important effects: promoting the self-renewal of uncommitted progenitors and directing equipotent progenitors in the same microenvironmental context to adopt distinct cell fates.
Mammalian hematopoiesis is a unique developmental process in which stem cells continue to generate vast numbers of diverse cell types throughout adult life. As in other systems, Notch appears to influence cell fate decisions at multiple steps during hematopoiesis, having effects that are determined by the presence of specific inductive signals and the precise maturational state of the cell. Defining the role of Notch signaling during hematopoiesis is complicated both by the number of Notch receptors and DSL ligands expressed by hematopoietic and stromal cells, and by the interactions of Notch with other signaling pathways within the intricate hematopoietic regulatory network.
Using a gene targeting strategy to conditionally express the different Notch receptors and DSL ligands at defined stages of in vitro ES cell differentiation and in vivo hematopoiesis, they hope to delineate the effects of Notch signaling on lineage specification and self-renewal of progenitors at various stages of hematopoietic commitment. Their previous studies, as well as those of other investigators, suggest that, in the appropriate context, Notch signaling delays differentiation and promotes expansion of hematopoietic stem/progenitor cells.
Therefore, one of their immediate goals is to use Notch signaling to generate large numbers of hematopoietic stem cells from ES cells; these ES cell-derived HSCs could provide a versatile alternative stem cell source for transplantation. Given the pervasive role of Notch during development, it's not surprising that aberrations in Notch signaling have been associated with a number of malignancies, including leukemias and lymphomas.
Thus, Dr. Milner hopes that their work will also provide insights as to how alterations in Notch signaling may contribute to pediatric malignancies, many of which represent normal developmental processes gone awry.
Hashmi, S*; Oliva, JL*; Liesveld, JL; Milner, LA; Phillips, GL II; Becker, MW. "The hematopoietic cell transplantation specific comorbidity Index and survival after extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation conditioning prior to allogeneic stem cell transplantation." Leukemia Research. 2013; 37(9): 1052-1056.
Liesveld,JL; Phillips,GL II; Becker, M; Constine, LS ; Friedberg, J; Andolina, JR; Milner, LA; DeBolt, J; Smudzin, T; Hyrien, O; Erickson-Miller, CL; Johnson, BM; Dawson, KL; Chen, Y. "A Phase 1 Trial of Eltrombopag in Patients Undergoing Stem
Cell Transplantation after Total Body Irradiation". Biology of Blood and Marrow Transplant. 2013; 19: 1745-1752.
Ban-Hoefen; M*; Kelly, JL*; Bernstein, SH; Liesveld, JL; Constine, LS; Becker, MW; Milner, LA; Phillips, GL; Friedberg, JW. "High-dose therapy and autologous stem cell transplant (HD-ASCT) for transformed non-Hodgkin lymphoma (NHL) in the rituximab era". Leukemia and Lymphoma. 2012; 53(5): 830-835.
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