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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 297-306
Inhibition of in vitro spontaneous apoptosis by IL-7 correlates
with Bcl-2 up-regulation, cortical/mature immunophenotype, and better
early cytoreduction of childhood T-cell acute lymphoblastic
leukemia
Leonid Karawajew,
Velia Ruppert,
Christian Wuchter,
Annett Kösser,
Martin Schrappe,
Bernd Dörken, and
Wolf-Dieter Ludwig
From the Department of Hematology, Oncology, and Tumor Immunology,
Robert-Rössle Clinic, Charité, Humboldt University of
Berlin, Berlin; and the Department of Pediatrics, Medical School of
Hannover, Hannover, Germany.
In normal T-cell development, IL-7 plays a nonredundant role as an
antiapoptic factor by regulating Bcl-2 expression in pro-T cells. In
the current study, we addressed the roles of IL-7 and related cytokines
as apoptosis-modulating factors in precursor T-cell acute lymphoblastic
leukemia (T-ALL). To this end, leukemic blasts from pediatric patients
with T-ALL were prospectively investigated as to their responsiveness
to IL-7, IL-4, and IL-2 (in terms of modulation of spontaneous
apoptosis, assessed by flow cytometry), cytokine receptor expression
profiles, and expression levels of Bcl-2 and Bax proteins. IL-7, in
contrast to IL-4 and IL-2, was highly efficient in apoptosis inhibition
, and this effect correlated with the expression levels of IL-7R
chain and with the up-regulation of Bcl-2 protein expression (P
< .0001). Subclassification of T-ALL samples (n = 130)
according to their in vitro IL-7 responses revealed that IL-7
refractory samples were more frequently positive for CD34 (P
< .0001) and the myeloid-associated antigen CD33 (P = .01), whereas IL-7 responsiveness was associated with an
expression of more mature differentiation-associated T-cell antigens
(CD1a, surface CD3, CD4/8; P < .05). Furthermore, the extent
of apoptosis inhibition by IL-7 in vitro quantitatively correlated with
early cytoreduction as determined by the prednisone peripheral blood response on day 8 and cytoreduction in the marrow on day 15 (n = 87;
P < .05). Multivariate analysis of the apoptosis-related parameters investigated, including spontaneous apoptosis, its inhibition by IL-7, and expression levels of Bcl-2 and Bax, showed that
only IL-7 responsiveness has an independent impact on early cytoreduction (P < .05), thus indicating a potential
prognostic relevance of IL-7 sensitivity in T-ALL.
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