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Blood, 1 January 2002, Vol. 99, No. 1, pp. 252-257
NEOPLASIA
Constitutive activity of signal transducer and activator of
transcription 3 protein in acute myeloid leukemia blasts is associated
with short disease-free survival
Mustafa Benekli,
Zheng Xia,
Kathleen A. Donohue,
Laurie A. Ford,
Lynda A. Pixley,
Maria R. Baer,
Heinz Baumann, and
Meir Wetzler
From the Leukemia Section, Department of Medicine,
Department of Cancer Prevention, Epidemiology and Biostatistics, and
Department of Molecular and Cellular Biology, Roswell Park Cancer
Institute, Buffalo, NY.
Signal transducer and activator of transcription (STAT) proteins
are involved in hematopoietic cytokine receptor signaling pathways that
regulate cell proliferation, differentiation, and survival. STATs are
dysregulated in acute myeloid leukemia (AML); mechanisms of
dysregulation include constitutive activation and truncation of the
C-terminal transactivation domain; the latter results in a  isoform
that has a trans-dominant negative effect on gene induction mediated by
the full-length STAT form. It was hypothesized that constitutive
STAT activity might correlate with unfavorable treatment outcome in
AML. Pretreatment bone marrow samples from 63 adult patients with AML
were analyzed by electrophoretic mobility shift assay for the presence
of STAT DNA-binding activity. Isoforms and relative levels of STAT
proteins were determined by immunoblotting. Constitutive STAT3 activity
was detected in samples from 28 (44%) patients. Pretreatment clinical
characteristics, expression of STAT/ isoforms, and treatment
regimens did not differ significantly between patients with and without
constitutive STAT3 activity. Disease-free survival (DFS) was
significantly shorter in patients with than in patients without
constitutive STAT3 activity (median 8.7 vs 20.6 months;
P = .01). Overall survival did not differ significantly.
The subgroup of patients with constitutive STAT3 activity and the
STAT3 isoform had the shortest DFS (P = .006) and
shorter overall survival (P = .049) than all other patients. Whether adverse treatment outcome is attributable to constitutive STAT activity itself or to a process that leads to constitutive STAT activity remains to be determined. This is the first
demonstration of a prognostic significance for STAT proteins in a malignancy.
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