Medical Biology - Research Publications

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Author: Loughran, Stephen ×

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    Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome
    Ng, AP ; Hyland, CD ; Metcalf, D ; Carmichael, CL ; Loughran, SJ ; Di Rago, L ; Kile, BT ; Alexander, WS (AMER SOC HEMATOLOGY, 2010-05-13)
    Down syndrome is characterized by multiple phenotypic manifestations associated with trisomy of chromosome 21. The transient myeloproliferative disorder and acute megakaryocytic leukemia associated with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown. Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(17(16))65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion. Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(17(16))65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.
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    Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice
    Ng, Ashley P. ; Loughran, Stephen J. ; METCALF, DONALD ; Hyland, Craig D. ; deGraaf, Carolyn A. ; Hu, Yifang ; Smyth, Gordon K. ; Hilton, Douglas J. ; Kile, Benjamin T. ; ALEXANDER, WARREN (American Society of Hematology, 2011)
    Hematopoietic stem cells (HSCs) are rare residents of the bone marrow responsible for the lifelong production of blood cells. Regulation of the balance between HSC self renewal and differentiation is central to hematopoiesis, allowing precisely regulated generation of mature blood cells at steady-state and expanded production at times of rapid need, as well as maintaining ongoing stem cell capacity. Erg, a member of the Ets family of transcription factors, is deregulated in cancers and while Erg is known to be required for regulation of adult HSCs, its precise role has not been defined. We show here that although heterozygosity for functional Erg is sufficient for adequate steady state HSC maintenance, Erg+/Mld2 mutant mice exhibit impaired HSC self-renewal following bone marrow transplantation or during recovery from myelotoxic stress. Moreover, while mice functionally compromised for either Erg or Mpl, the receptor for TPO, a key regulator of HSC quiescence, maintained sufficient HSC activity to sustain hematopoiesis, Mpl-/- Erg+/Mld2 compound mutant mice displayed exacerbated stem cell deficiencies and bone marrow failure. Thus, Erg is a critical regulator of adult HSCs, essential for maintaining self renewal at times of high HSC cycling.
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    Murine hematopoietic blast colony-forming cells and their progeny have distinctive membrane marker profiles
    Metcalf, D ; Ng, AP ; Loughran, SJL ; Phipson, B ; Smyth, GK ; Di Rago, L ; Mifsud, S (NATL ACAD SCIENCES, 2009-11-10)
    Two distinct bone marrow-derived blast colony-forming cells can generate colonies of lineage-restricted progenitor cells in agar cultures of murine bone marrow. Both cell types selectively had a Kit(+) ScaI(+) phenotype distinguishing them from most lineage-restricted progenitor cells. Multicentric blast colony-forming cells stimulated by stem cell factor plus interleukin-6 (IL-6) (BL-CFC-S) were separable from most dispersed blast colony-forming cells stimulated by Flt3 ligand and IL-6 (BL-CFC-F) using CD34 and Flt3R probes. Multicentric BL-CFC-S cofractionated with colony-forming units, spleen (CFU-S) supporting the possibility that the 2 cells may be identical. The colony populations generated by BL-CFC-S were similar in their phenotype and proliferative capacity to progenitor cells in whole bone marrow but the progeny of BL-CFC-F were skewed with an abnormally high proportion of Kit(-) Flt3R(+) cells whose clonogenic cells tended to generate only macrophage progeny. Both blast colony populations had a high percentage of GR1(+) and Mac1(+) cells but BL-CFC-F colonies also contained a significant population of B220(+) and IL-7R(+) cells relevant to the superior ability of BL-CFC-F colony cells to generate B lymphocytes and the known dependency of this process on Flt3 ligand and IL-7. The commitment events and phenotypic changes during the generation of differing progenitor cells in blast colonies can now be clonally analyzed in a convenient in vitro culture system.