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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1766-1775
NEOPLASIA
Overexpression of SOCS-2 in advanced stages of chronic
myeloid leukemia: possible inadequacy of a negative feedback
mechanism
Beate Schultheis,
Melina Carapeti-Marootian,
Andreas Hochhaus,
Andreas Wei er,
John M. Goldman, and
Junia V. Melo
From the Department of Haematology, Faculty of
Medicine, Imperial College of Science, Technology and Medicine, London,
United Kingdom and III. Medizinische Klinik, Universitätsklinikum
Mannheim, Fakultät für Klinische Medizin Mannheim der
Universität Heidelberg, Germany.
Constitutive activation of the BCR-ABL tyrosine kinase
is fundamental to the pathogenesis of chronic myeloid leukemia (CML). STI571 inhibits this activity and modulates the transcription of
several genes. It was shown by differential display that the suppressor
of cytokine signaling-2 (SOCS-2) gene was down-regulated by
STI571 treatment in 14 of 16 BCR-ABL-positive cell lines
and in 2 BCR-ABL-transfected murine lines, but not in
BCR-ABL-negative counterparts. The effect was maximal at 2 hours and persisted for at least 24 hours after exposure to 1 µM
STI571, whereas SOCS-1 and SOCS-3 expression
were unaffected. Baseline levels of SOCS-2 were
significantly higher in BCR-ABL-positive as compared with BCR-ABL-negative cell lines. It was similar in leukocytes
and CD34+ cells from healthy persons (n = 44) and
patients with CML in chronic phase (CP; n = 60) but significantly
increased in patients with CML in blast crisis (BC; n = 20)
(P < .0001). Mononuclear cells (MNCs) from 3 of 4 patients with CML in BC showed a 2-fold to 12-fold down-regulation of
SOCS-2 levels on in vitro exposure to STI571; moreover, a
2-fold to 11-fold decrease in SOCS-2 was observed in MNCs
from 7 of 8 patients with CML in BC who responded to treatment with
STI571. Refractoriness to STI571 or relapse after initial response was
accompanied by augmentation of SOCS-2 expression. Ectopic
overexpression of SOCS-2 in 32Dp210 cells slowed growth,
inhibited clonogenicity, and increased their motility and sensitivity
to STI571. Overall, the results suggest that SOCS-2 is a
component of a negative feedback mechanism; it is induced by Bcr-Abl
but cannot reverse its overall growth-promoting effects in blastic transformation.
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