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Blood, 15 September 2001, Vol. 98, No. 6, pp. 1773-1781
HEMATOPOIESIS
Chronic myelogenous leukemia blast cell proliferation is
inhibited by peptides that disrupt Grb2-SoS complexes
Christian Kardinal,
Birgit Konkol,
Hui Lin,
Manfred Eulitz,
Enrico K. Schmidt,
Zeev Estrov,
Moshe Talpaz,
Ralph B. Arlinghaus, and
Stephan M. Feller
From the Laboratory of Molecular Oncology, Institut
für Medizinishe Strahleukunde und Zellforschung,
Universität Würzburg, Germany; Klinische Molekularbiologie
und Tumorgenetik, Forschungszentrum für Umwelt und Gesundheit,
Munich, Germany; M. D. Anderson Cancer Center, Houston,
TX; and Cell Signalling Laboratory, Imperial Cancer Research Fund,
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford,
United Kingdom.
Chronic myelogenous leukemia (CML) is commonly characterized by the
presence of the p210Bcr-Abl oncoprotein. Many downstream
effectors of Bcr-Abl have been described, including activation of the
Grb2-SoS-Ras-MAP kinase (Erk) pathway. The precise contributions of
these signal-transduction proteins in CML blast cells in human patients
are not yet well defined. To gain further insight into the importance
of Grb2 for CML, peptides that disrupt Grb2-SoS complexes were tested.
These high-affinity Grb2-binding peptides (HAGBPs) can
autonomously shuttle into cells and function by binding to the
N-terminal SH3 domain of Grb2. The HAGBPs were analyzed for their
effects on Bcr-Abl-expressing cell lines and freshly isolated CML
blast cells from patients. They induced a dramatic decrease in the
proliferation of CML cell lines. This was not observed with
point-mutated control peptides with abolished Grb2SH3(N) binding. As
expected, Grb2-SoS complexes were greatly diminished in the
HAGBP-treated cells, and MAP kinase activity was significantly reduced
as determined by an activation-specific phospho-MAPK antibody.
Furthermore, cell fractions that are enriched for blast cells from CML
patients with active disease were also incubated with the Grb2 blocker
peptides. The HAGBPs led to a significant proliferation reduction of
these cells in the majority of the isolates, but not in all patients'
cells. These results show that, in addition to the direct targeting of
Bcr-Abl, selective inhibition of Grb2 protein complexes may be a
therapeutic option for a significant number of CML patients.
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