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Growth of erythroid colonies in chronic myelogenous leukemia is independent
of erythropoietin only in the presence of steel factor
C Issaad and W Vainchenker
INSERM U 362, Institut Gustave Roussy, Villejuif, France.
The mechanisms of the chronic myeloid leukemia (CML) clones proliferative
advantage over normal clones are currently unknown. They may involve an
insensitivity to a negative regulation of a growth factor-independent
proliferation. Clonogenic progenitors from CML patient blood or marrow in
chronic phase were grown either in the presence or absence of recombinant
growth factors. No erythroid colonies were observed in the absence of any
cytokine. In contrast, erythroid colonies composed of fully mature
hemoglobinized erythroblasts (day 12 burst-forming units-erythroid) were
obtained in the presence of Steel factor (SF) alone. Addition of
erythropoietin (Epo) to SF either had no effect on the cloning efficiency
or increased up to 50% the number of erythroid colonies. No erythroid
growth was observed when cultures were stimulated by interleukin-3 or
granulocyte- macrophage colony-stimulating factor alone. Similar erythroid
growth in the presence of SF but without Epo was obtained in "serum-free"
cultures when purified blood CML CD34+ cells were grown. This growth of
erythroid colonies in the absence of Epo was not accounted for by an
autocrine stimulation loop by Epo, because neutralizing antibodies against
Epo did not inhibit it. This abnormal response to growth factor was
specifically observed in the CML clone, as shown by the presence of the
BCR-ABL transcript in all of these erythroid colonies. The direct
implication of BCR-ABL was further documented (1) by studies of alpha-
interferon-treated patients with a chimerism in which the abnormal growth
correlates with the presence of the malignant clone and (2) by the use of
antisense oligonucleotide against BCR-ABL transcript, which abrogated this
abnormal growth. Finally, erythroid growth in the SF presence was greatly
diminished by herbimycin A, whereas, at the same concentration, this
tyrosine kinase inhibitor had no marked effect on erythroid colony
formation in the presence of SF plus Epo on CML or normal marrow cells.
This result suggests that the BCR-ABL kinase activity leads directly to
this Epo-independent terminal differentiation requiring, however, the
presence of SF.
Volume 84,
Issue 10,
pp. 3447-3456,
11/15/1994
Copyright © 1994 by The American Society of Hematology
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