Dr. Milner's research interests are:

1) Stem Cells
2) Hematopoiesis
3) Transplantation
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-dervived 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.

• Reid R, Bennett JM, Becker M, Chen Y, Milner L, Phillips Ii GL, Liesveld J. Use of eltrombopag, a thrombopoietin receptor agonist, in post-transplantation thrombocytopenia. Am J Hematol. 2012 Jul; 87(7):743-5.
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• Ban-Hoefen M, Kelly JL, Bernstein SH, Liesveld J, Constine L, Becker M, Milner L, Phillips G, Friedberg JW. High-dose therapy and autologous stem cell transplant for transformed non-Hodgkin lymphoma in the rituximab era. Leuk Lymphoma. 2012 May; 53(5):830-5.
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• Milner LA, Becker MW, Bernstein SH, Bruckner L, Friedberg JW, Holland GA, Ifthikharuddin JJ, Liesveld JL, Mathes EJ, Menchel HL, Mullen CA, Sasson T, Phillips GL. Intra-arterial methylprednisolone for the management of steroid-refractory acute gastrointestinal and hepatic graft versus host disease. Am J Hematol. 2011 Aug; 86(8):712-4.
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• Phillips GL, Bernstein SH, Liesveld JL, Abboud CN, Becker MW, Constine LS, Ifthikharuddin JJ, Loughner JE, Milner LA, Vesole DH, Friedberg JW. A Phase I trial: dose escalation of melphalan in the "BEAM" regimen using amifostine cytoprotection. Biol Blood Marrow Transplant. 2011 Jul; 17(7):1033-42.
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• Karp JM, Milner LA. Oral eruption cysts in a child with hepatoblastoma. J Pediatr Hematol Oncol. 2009 Jul; 31(7):509-11.
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• Weber JM, Forsythe SR, Christianson CA, Frisch BJ, Gigliotti BJ, Jordan CT, Milner LA, Guzman ML, Calvi LM. Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells. Bone. 2006 Sep; 39(3):485-93.
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• Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003 Oct 23; 425(6960):841-6.
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• Woolfrey AE, Anasetti C, Storer B, Doney K, Milner LA, Sievers EL, Carpenter P, Martin P, Petersdorf E, Appelbaum FR, Hansen JA, Sanders JE. Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood. 2002 Mar 15; 99(6):2002-8.
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• Inglés-Esteve J, Espinosa L, Milner LA, Caelles C, Bigas A. Phosphorylation of Ser2078 modulates the Notch2 function in 32D cell differentiation. J Biol Chem. 2001 Nov 30; 276(48):44873-80.
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• Benito AI, Milner LA, Leisenring W, Deeg HJ, Woolfrey AE. Absence of major histocompatibility class II expression does not impair hematopoiesis in mice. Exp Hematol. 2001 Sep; 29(9):1070-5.
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• Huppert SS, Le A, Schroeter EH, Mumm JS, Saxena MT, Milner LA, Kopan R. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature. 2000 Jun 22; 405(6789):966-70.
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• Milner LA, Bigas A. Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood. 1999 Apr 15; 93(8):2431-48.
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• Woolfrey AE, Gooley TA, Sievers EL, Milner LA, Andrews RG, Walters M, Hoffmeister P, Hansen JA, Anasetti C, Bryant E, Appelbaum FR, Sanders JE. Bone marrow transplantation for children less than 2 years of age with acute myelogenous leukemia or myelodysplastic syndrome. Blood. 1998 Nov 15; 92(10):3546-56.
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• Bigas A, Martin DI, Milner LA. Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Mol Cell Biol. 1998 Apr; 18(4):2324-33.
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• Li L, Milner LA, Deng Y, Iwata M, Banta A, Graf L, Marcovina S, Friedman C, Trask BJ, Hood L, Torok-Storb B. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity. 1998 Jan; 8(1):43-55.
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• Milner LA, Bigas A, Kopan R, Brashem-Stein C, Bernstein ID, Martin DI. Inhibition of granulocytic differentiation by mNotch1. Proc Natl Acad Sci U S A. 1996 Nov 12; 93(23):13014-9.
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• Milner LA, Kopan R, Martin DI, Bernstein ID. A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors. Blood. 1994 Apr 15; 83(8):2057-62.
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• Willems van Dijk K, Milner LA, Sasso EH, Milner EC. Chromosomal organization of the heavy chain variable region gene segments comprising the human fetal antibody repertoire. Proc Natl Acad Sci U S A. 1992 Nov 1; 89(21):10430-4.
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• Van Dijk KW, Milner LA, Milner EC. Mapping of human H chain V region genes (VH4) using deletional analysis and pulsed field gel electrophoresis. J Immunol. 1992 May 1; 148(9):2923-31.
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• Gustafson GL, Milner LA. Occurrence of N-acetylglucosamine-1-phosphate in proteinase I from Dictyostelium discoideum. J Biol Chem. 1980 Aug 10; 255(15):7208-10.
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• Gustafson GL, Milner LA. Immunological relationship between beta-N-acetyglucosaminidase and proteinase I from Dictyostelium discoideum. Biochem Biophys Res Commun. 1980 Jun 30; 94(4):1439-44.
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• Gustafson GL, Thon LA. Purification and characterization of a proteinase from Dictyostelium discoideum. J Biol Chem. 1979 Dec 25; 254(24):12471-8.
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• Gustafson GL, Thon LA. Evidence for phosphoryl moieties in a proteinase from Dictyostelium discoideum. Biochem Biophys Res Commun. 1979 Feb 14; 86(3):667-73.
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