|
|
 Previous Article | Table of Contents | Next Article 
Selection of myeloid progenitors lacking BCR/ABL mRNA in chronic
myelogenous leukemia patients after in vitro treatment with the tyrosine
kinase inhibitor genistein
C Carlo-Stella, G Dotti, L Mangoni, E Regazzi, D Garau, A Bonati, C Almici, G Sammarelli, B Savoldo, MT Rizzo and V Rizzoli
Department of Hematology, University of Parma, Italy.
Chronic myelogenous leukemia (CML) is a clonal disorder of the
hematopoietic stem cell characterized by a chimeric BCR/ABL gene giving
rise to a 210-kD fusion protein with dysregulated tyrosine kinase activity.
We investigated the effect of genistein, a protein tyrosine kinase
inhibitor, on the in vitro growth of CML and normal marrow- derived
multi-potent (colony-forming unit-mix [CFU-Mix]), erythroid (burst-forming
unit-erythroid [BFU-E]), and granulocyte-macrophage (colony-forming
unit-granulocyte-macrophage [CFU-GM]) hematopoietic progenitors. Continuous
exposure of CML and normal marrow to genistein induced a statistically
significant and dose-dependent suppression of colony formation. Genistein
doses causing 50% inhibition of CML and normal progenitors were not
significantly different for CFU-Mix (27 mumol/L v 23 mumol/L), BFU-E (31
mumol/L v 29 mumol/L), and CFU-GM (40 mumol/L v 32 mumol/L v 32 mumol/L).
Preincubation of CML and normal marrow with genistein (200 mumol/ L for 1
to 18 hours) induced a time- dependent suppression of progenitor cell
growth, while sparing a substantial proportion of long-term
culture-initiating cells (LTC-IC) from CML (range, 91% +/- 9% to 32% +/-
3%) and normal marrow (range, 85% +/- 8% to 38% +/- 9%). Analysis of
individual CML colonies for the presence of the hybrid BCR/ABL mRNA by
reverse transcription-polymerase chain reaction (RT-PCR) showed that
genistein treatment significantly reduced the mean +/- SD percentage of
marrow BCR/ABL+ progenitors both by continuous exposure (76% +/- 18% v 24%
+/- 12%, P < or = .004) or preincubation (75% +/- 16% v 21% +/- 10%, P
< or = .002) experiments. Preincubation with genistein reduced the
percentage of leukemic LTC-IC from 87% +/- 12% to 37% +/- 12% (P < or =
.003). Analysis of individual colonies by cytogenetics and RT-PCR confirmed
that genistein-induced increase in the percentage of nonleukemic
progenitors was not due to suppression of BCR/ABL transcription. Analysis
of nuclear DNA fragmentation by DNA gel electrophoresis and terminal
deoxynucleotidyl transferase assay showed that preincubation of CML
mononuclear and CD34+ cells with genistein induced significant evidence of
apoptosis. These observations show that genistein is capable of (1)
exerting a strong antiproliferative effect on CFU-Mix, BFU-E, and CFU-GM
while sparing the more primitive LTC-IC and (2) selecting benign
hematopoietic progenitors from CML marrow, probably through an apoptotic
mechanism.
Volume 88,
Issue 8,
pp. 3091-3100,
10/15/1996
Copyright © 1996 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:
|
|
|
|
 
M. Deininger, E. Buchdunger, and B. J. Druker
The development of imatinib as a therapeutic agent for chronic myeloid leukemia
Blood,
April 1, 2005;
105(7):
2640 - 2653.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. W. N. Deininger and B. J. Druker
Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib
Pharmacol. Rev.,
September 1, 2003;
55(3):
401 - 423.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Svingen, A. Tefferi, T. J. Kottke, G. Kaur, V. L. Narayanan, E. A. Sausville, and S. H. Kaufmann
Effects of the bcr/abl Kinase Inhibitors AG957 and NSC 680410 on Chronic Myelogenous Leukemia Cells in Vitro
Clin. Cancer Res.,
January 1, 2000;
6(1):
237 - 249.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Kantarjian, J. V. Melo, S. Tura, S. Giralt, and M. Talpaz
Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies
Hematology,
January 1, 2000;
2000(1):
90 - 109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Rizzo, E. Regazzi, D. Garau, L. Akard, M. Dugan, H. S. Boswell, V. Rizzoli, and C. Carlo-Stella
Induction of Apoptosis by Arachidonic Acid in Chronic Myeloid Leukemia Cells
Cancer Res.,
October 1, 1999;
59(19):
5047 - 5053.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Carlo-Stella, E. Regazzi, G. Sammarelli, S. Colla, D. Garau, A. Gazit, B. Savoldo, D. Cilloni, A. Tabilio, A. Levitzki, et al.
Effects of the Tyrosine Kinase Inhibitor AG957 and an Anti-Fas Receptor Antibody on CD34+ Chronic Myelogenous Leukemia Progenitor Cells
Blood,
June 1, 1999;
93(11):
3973 - 3982.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
