|
|
 Previous Article | Table of Contents | Next Article 
Blood, 15 November 2000, Vol. 96, No. 10, pp. 3310-3321
PLENARY PAPER
Hypersensitivity of circulating progenitor cells to megakaryocyte
growth and development factor (PEG-rHu MGDF) in essential
thrombocythemia
Arthur A. Axelrad,
Denise Eskinazi,
Paulo N. Correa, and
Dominick Amato
From the Department of Anatomy and Cell Biology and
Medical Biophysics, University of Toronto; and the Department of
Medicine (Hematology/ Oncology), Mt Sinai Hospital, Toronto, Ontario,
Canada.
Hematopoietic progenitor cells in 2 myeloproliferative disorders,
juvenile chronic myelomonocytic leukemia and polycythemia vera, are
known to be hypersensitive to cytokines that control normal progenitor
cell proliferation, differentiation, and survival in their respective
granulocyte/macrophage and erythroid lineages. Because thrombopoietin
controls these functions in the normal megakaryocytic lineage, we asked
the question: Are megakaryocytic progenitor cells in the
myeloproliferative disorder essential thrombocythemia (ET)
hypersensitive to thrombopoietin? Peripheral blood mononuclear cells
from patients with ET, or secondary (reactive) thrombocytosis (2°T),
or healthy volunteers were grown in strictly serum-free agarose culture
containing interleukin 3 (IL-3) and all-trans-retinoic acid, with
various concentrations of PEG-rHu megakaryocyte growth and development
factor (MGDF). The concentration of cytokine at half-maximum colony
number served as a measure of progenitor cell sensitivity.
Hypersensitivity to PEG-rHu MGDF was found in circulating progenitors
from 18 of 20 (90%) informative patients with presumptive diagnosis
ET, 1 of 8 (12.5%) 2 °T patients, and none of the 22 healthy
volunteers. Median MGDF sensitivity ratio in ET patients was
approximately 53 times greater than in the controls. This
hypersensitivity, which was also directed to rHu thrombopoietin, was
highly specific with respect to cytokine, disease, and cell lineage. We
propose that, despite their single pluripotential cell origin, the
different clinicopathologic phenotypes in different chronic
myeloproliferative disorders are determined by lineage-restricted
hypersensitivities of hematopoietic progenitor cells to endogenous
cytokines. This work emphasizes the importance of stringent serum-free
conditions for revealing true sensitivities to cytokines. The findings
also offer a basis for evolving a positive test for ET, a diagnosis now
made essentially by exclusion.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
K. M. Sakamoto and D. A. Frank
CREB in the Pathophysiology of Cancer: Implications for Targeting Transcription Factors for Cancer Therapy
Clin. Cancer Res.,
April 15, 2009;
15(8):
2583 - 2587.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sayyah, A. Magis, D. A. Ostrov, R. W. Allan, R. C. Braylan, and P. P. Sayeski
Z3, a novel Jak2 tyrosine kinase small-molecule inhibitor that suppresses Jak2-mediated pathologic cell growth
Mol. Cancer Ther.,
August 1, 2008;
7(8):
2308 - 2318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. I. Schafer
Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia
Blood,
June 1, 2006;
107(11):
4214 - 4222.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. M. Jamieson, J. Gotlib, J. A. Durocher, M. P. Chao, M. R. Mariappan, M. Lay, C. Jones, J. L. Zehnder, S. L. Lilleberg, and I. L. Weissman
The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation
PNAS,
April 18, 2006;
103(16):
6224 - 6229.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. Jones, S. Kreil, K. Zoi, K. Waghorn, C. Curtis, L. Zhang, J. Score, R. Seear, A. J. Chase, F. H. Grand, et al.
Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders
Blood,
September 15, 2005;
106(6):
2162 - 2168.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tefferi and D. G. Gilliland
The JAK2V617F Tyrosine Kinase Mutation in Myeloproliferative Disorders: Status Report and Immediate Implications for Disease Classification and Diagnosis
Mayo Clin. Proc.,
July 1, 2005;
80(7):
947 - 958.
[Abstract]
[PDF]
|
|
|
|
|
|
|
K. Kaushansky
On the molecular origins of the chronic myeloproliferative disorders: it all makes sense
Blood,
June 1, 2005;
105(11):
4187 - 4190.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Kralovics, F. Passamonti, A. S. Buser, S.-S. Teo, R. Tiedt, J. R. Passweg, A. Tichelli, M. Cazzola, and R. C. Skoda
A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
N. Engl. J. Med.,
April 28, 2005;
352(17):
1779 - 1790.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kaushansky
On the Molecular Origins of the Chronic Myeloproliferative Disorders: It All Makes Sense
Hematology,
January 1, 2005;
2005(1):
533 - 537.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Tenedini, M. E. Fagioli, N. Vianelli, P. L. Tazzari, F. Ricci, E. Tagliafico, P. Ricci, L. Gugliotta, G. Martinelli, S. Tura, et al.
Gene expression profiling of normal and malignant CD34-derived megakaryocytic cells
Blood,
November 15, 2004;
104(10):
3126 - 3135.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. I. Schafer
Thrombocytosis
N. Engl. J. Med.,
March 18, 2004;
350(12):
1211 - 1219.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Liu, J. Jelinek, Y. D. Pastore, Y. Guan, J. F. Prchal, and J. T. Prchal
Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin
Blood,
April 15, 2003;
101(8):
3294 - 3301.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tefferi
Polycythemia Vera: A Comprehensive Review and Clinical Recommendations
Mayo Clin. Proc.,
February 1, 2003;
78(2):
174 - 194.
[Abstract]
[PDF]
|
|
|
|
|
