title: Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy.
abstract: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, the B-cell receptor (BCR) and nuclear factor- κB (NF-κB) pathways are activated in the lymph node (LN) microenvironment. Thus, model systems mimicking tumor-host interactions are important tools to study CLL biology and pathogenesis. We investigated whether the recently established NOD/scid/γc(null) (NSG) mouse xenograft model can recapitulate the effects of the human microenvironment. We assessed, therefore, tumor characteristics previously defined in LN-resident CLL cells, including proliferation, and activation of the BCR and NF-κB pathways. We found that the murine spleen (SP) microenvironment supported CLL cell proliferation and activation to a similar degree than the human LN, including induction of BCR and NF-κB signaling in the xenografted cells. Next, we used this model to study ibrutinib, a Bruton's tyrosine kinase inhibitor in clinical development. Ibrutinib inhibited BCR and NF-κB signaling induced by the microenvironment, decreased proliferation, induced apoptosis and reduced the tumor burden in vivo. Thus, our data demonstrate that the SP of xenografted NSG mice can, in part, recapitulate the role of the human LN for CLL cells. In addition, we show that ibrutinib effectively disrupts tumor-host interactions essential for CLL cell proliferation and survival in vivo.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S E M
authors.initials: SE
authors.lastname: Herman
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.forename: E M
authors.initials: EM
authors.lastname: McAuley
authors.forename: M M
authors.initials: MM
authors.lastname: Hsieh
authors.forename: S
authors.initials: S
authors.lastname: Pittaluga
authors.forename: M
authors.initials: M
authors.lastname: Raffeld
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Keyvanfar
authors.forename: C M
authors.initials: CM
authors.lastname: Chapman
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: J J
authors.initials: JJ
authors.lastname: Buggy
authors.forename: G
authors.initials: G
authors.lastname: Aue
authors.forename: J F
authors.initials: JF
authors.lastname: Tisdale
authors.forename: P
authors.initials: P
authors.lastname: Pérez-Galán
authors.forename: A
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D000818:Animals; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D008954:Models, Biological; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine