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.
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-7Ralpha 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.
Karawajew
L
L
Department of Hematology, Oncology, and Tumor Immunology, Robert-Rössle Clinic, Charité, Humboldt University of Berlin, Berlin, Germany. karawajew@rrkberlin.de
Ruppert
V
V
Wuchter
C
C
Kösser
A
A
Schrappe
M
M
Dörken
B
B
Ludwig
W D
WD
D017209:Apoptosis / Q000187:drug effects*; D001752:Blast Crisis / Q000097:blood / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D002648:Child; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000276:immunology* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics; D018121:Receptors, Cytokine / Q000032:analysis; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D007376:Interleukin-2; D015851:Interleukin-7; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018121:Receptors, Cytokine; D051028:bcl-2-Associated X Protein; D015847:Interleukin-4