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Mechanistic Insights into CpG DNA and IL-15 Synergy in Promoting B Cell Chronic Lymphocytic Leukemia Clonal Expansion.
Gupta, Rashmi; Yan, Xiao J; Barrientos, Jacqueline; Kolitz, Jonathan E; Allen, Steven L; Rai, Kanti; Chiorazzi, Nicholas; Mongini, Patricia K A.
Afiliación
  • Gupta R; The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.
  • Yan XJ; The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.
  • Barrientos J; Department of Medicine, North Shore University Hospital-Long Island Jewish Medical Center, Northwell Health, Manhasset, NY 11303.
  • Kolitz JE; The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.
  • Allen SL; Department of Medicine, North Shore University Hospital-Long Island Jewish Medical Center, Northwell Health, Manhasset, NY 11303.
  • Rai K; Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549; and.
  • Chiorazzi N; The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.
  • Mongini PKA; Department of Medicine, North Shore University Hospital-Long Island Jewish Medical Center, Northwell Health, Manhasset, NY 11303.
J Immunol ; 201(5): 1570-1585, 2018 09 01.
Article en En | MEDLINE | ID: mdl-30068596
Malignant cell growth within patients with B cell chronic lymphocytic leukemia (B-CLL) is largely restricted to lymphoid tissues, particularly lymph nodes. The recent in vitro finding that TLR-9 ligand (oligodeoxynucleotide [ODN]) and IL-15 exhibit strong synergy in promoting B-CLL growth may be particularly relevant to growth in these sites. This study shows IL-15-producing cells are prevalent within B-CLL-infiltrated lymph nodes and, using purified B-CLL cells from blood, investigates the mechanism for ODN and IL-15 synergy in driving B-CLL growth. ODN boosts baseline levels of phospho-RelA(S529) in B-CLL and promotes NF-κB-driven increases in IL15RA and IL2RB mRNA, followed by elevated IL-15Rα and IL-2/IL-15Rß (CD122) protein. IL-15→CD122 signaling during a critical interval, 20 to 36-48 h following initial ODN exposure, is required for optimal induction of the cycling process. Furthermore, experiments with neutralizing anti-IL-15 and anti-CD122 mAbs indicate that clonal expansion requires continued IL-15/CD122 signaling during cycling. The latter is consistent with evidence of heightened IL2RB mRNA in the fraction of recently proliferated B-CLL cells within patient peripheral blood. Compromised ODN+IL-15 growth with limited cell density is consistent with a role for upregulated IL-15Rα in facilitating homotypic trans IL-15 signaling, although there may be other explanations. Together, the findings show that ODN and IL-15 elicit temporally distinct signals that function in a coordinated manner to drive B-CLL clonal expansion.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oligodesoxirribonucleótidos / Leucemia Linfocítica Crónica de Células B / Transducción de Señal / Interleucina-15 / Proliferación Celular Límite: Female / Humans Idioma: En Revista: J Immunol Año: 2018 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oligodesoxirribonucleótidos / Leucemia Linfocítica Crónica de Células B / Transducción de Señal / Interleucina-15 / Proliferación Celular Límite: Female / Humans Idioma: En Revista: J Immunol Año: 2018 Tipo del documento: Article