|
|
 Previous Article | Table of Contents | Next Article 
Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Prevents Dissemination and Induces Remission of Juvenile Myelomonocytic Leukemia in Engrafted Immunodeficient Mice
Per O. Iversen,
Ian D. Lewis,
Suzanne Turczynowicz,
Henrik Hasle,
Charlotte Niemeyer,
Kjeld Schmiegelow,
Stan Bastiras,
Andrea Biondi,
Timothy P. Hughes, and
Angel F. Lopez
From the Divisions of Human Immunology and Haematology of the Hanson Centre for Cancer Research, IMVS, Adelaide, S.A., Australia; Department of Pediatrics, Aarhus University Hospital Skejby, Denmark; Department of Pediatrics, University of Freiburg, Freiburg, Germany; Pediatric Clinic II, The Juliane Marie Center, Rigshospitalet, Copenhagen, Denmark; BresaGen Limited, Thebarton, S.A., Australia; Department of Pediatrics, University of Milano, S. Gerardo Hospital, Monza, Italy.
Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor  (TNF) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNF monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.
Blood, Vol. 90 No. 12 (December 15), 1997:
pp. 4910-4917
© 1997 by The American Society of Hematology.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. Kim, K. Morgan, D. E. Hasz, S. M. Wiesner, J. O. Lauchle, J. L. Geurts, M. D. Diers, D. T. Le, S. C. Kogan, L. F. Parada, et al.
{beta} common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice
Blood,
February 15, 2007;
109(4):
1687 - 1691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ohtsuka, A. Manabe, H. Kawasaki, D. Hasegawa, Y. Zaike, S. Watanabe, T. Tanizawa, T. Nakahata, and K. Tsuji
RAS-blocking bisphosphonate zoledronic acid inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia cells in vitro
Blood,
November 1, 2005;
106(9):
3134 - 3141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. T. Le, N. Kong, Y. Zhu, J. O. Lauchle, A. Aiyigari, B. S. Braun, E. Wang, S. C. Kogan, M. M. Le Beau, L. Parada, et al.
Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder
Blood,
June 1, 2004;
103(11):
4243 - 4250.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Jakupovic, V. L. Grandage, D. C. Linch, and A. Khwaja
Lack of effect of the human GM-CSF analog E21R on the survival of primary human acute myeloid leukemia cells
Blood,
April 15, 2004;
103(8):
3230 - 3232.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Ingram, M. J. Wenning, K. Shannon, and D. W. Clapp
Leukemic potential of doubly mutant Nf1 and Wv hematopoietic cells
Blood,
March 1, 2003;
101(5):
1984 - 1986.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. McClure, T. R. Hercus, B. A. Cambareri, J. M. Woodcock, C. J. Bagley, G. J. Howlett, and A. F. Lopez
Molecular assembly of the ternary granulocyte-macrophage colony-stimulating factor receptor complex
Blood,
February 15, 2003;
101(4):
1308 - 1315.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. O. Iversen, P. D. Emanuel, and M. Sioud
Targeting Raf-1 gene expression by a DNA enzyme inhibits juvenile myelomonocytic leukemia cell growth
Blood,
May 13, 2002;
99(11):
4147 - 4153.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Bernard, C. Thomas, J. F. Emile, T. Hercus, B. Cassinat, C. Chomienne, and J. Donadieu
Transient hematologic and clinical effect of E21R in a child with end-stage juvenile myelomonocytic leukemia
Blood,
April 1, 2002;
99(7):
2615 - 2616.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Arceci, B. J. Longley, and P. D. Emanuel
Atypical Cellular Disorders
Hematology,
January 1, 2002;
2002(1):
297 - 314.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. D. Emanuel, R. C. Snyder, T. Wiley, B. Gopurala, and R. P. Castleberry
Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors
Blood,
January 15, 2000;
95(2):
639 - 645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. O. Iversen and M. Sioud
Modulation of Granulocyte-Macrophage Colony-Stimulating Factor Gene Expression by a Tumor Necrosis Factor alpha Specific Ribozyme in Juvenile Myelomonocytic Leukemic Cells
Blood,
December 1, 1998;
92(11):
4263 - 4268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Zhang and R. Ren
Bcr-Abl Efficiently Induces a Myeloproliferative Disease and Production of Excess Interleukin-3 and Granulocyte-Macrophage Colony-Stimulating Factor in Mice: A Novel Model for Chronic Myelogenous Leukemia
Blood,
November 15, 1998;
92(10):
3829 - 3840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-Y. Zhang, T. A. Vik, J. W. Ryder, E. F. Srour, T. Jacks, K. Shannon, and D. Wade Clapp
Nf1 Regulates Hematopoietic Progenitor Cell Growth and Ras Signaling in Response to Multiple Cytokines
J. Exp. Med.,
June 1, 1998;
187(11):
1893 - 1902.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
