title: Common gamma chain-signaling cytokines promote proliferation of T-cell acute lymphoblastic leukemia.
abstract: OBJECTIVE
  The identification of signals critical for the pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) should contribute to the development of novel, more effective therapeutic strategies. Common gamma-chain signaling cytokines (gammac-cytokines) - interleukins 2, 4, 7, 9 and 15 - differentially regulate T-cell development, survival, proliferation and differentiation. Although studies exist on some individual cytokines, no comprehensive analysis of the effects of the Zc-cytokine family on malignant T cells has been reported. Here, we examined the effect of Zc-cytokines on T-ALL proliferation.
  
  
  METHODS
  Primary leukemic cells were collected at diagnosis from the blood or bone marrow of children with T-ALL. The cells were immunophenotyped and classified according to maturation stage. Proliferative responses to gammac-cytokines were assessed by 3H-thymidine incorporation.
  
  
  RESULTS
  All gammac-cytokines promoted proliferation of primary T-ALL cells. Interleukin (IL)-7 was the cytokine that most frequently induced leukemic cell proliferation and promoted the most robust responses. IL-4 preferentially stimulated proliferation of samples with a more mature immunophenotype, whereas CD1a-positive cortical T-ALL cells were less responsive to IL-9. Finally, combinations of two Zc-cytokines showed synergistic or additive proliferative effects.
  
  
  CONCLUSIONS
  This study indicates that all the gammac-cytokines tested can stimulate proliferation of leukemic T cells and suggests that synergistic effects may occur in vivo. We present the first demonstration that IL-9 and IL-15 can provide a proliferative signal to T-ALL cells. Importantly, our results support the hypothesis that IL-7 may function as a critical regulator of T-ALL and that its activity may be potentiated by other Zc-cytokines.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joao T
authors.initials: JT
authors.lastname: Barata
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Keenan
authors.forename: Ana
authors.initials: A
authors.lastname: Silva
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Boussiotis
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
mesh_terms: D019898:Autocrine Communication; D001773:Blood Cells / Q000187:drug effects / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002648:Child; D004357:Drug Synergism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D016906:Interleukin-9 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology / Q000503:physiopathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
chemical_list: C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D016906:Interleukin-9; D007378:Interleukins; D018123:Receptors, Interleukin; D015847:Interleukin-4