title: Nanowire-mediated delivery enables functional interrogation of primary immune cells: application to the analysis of chronic lymphocytic leukemia.
abstract: A circuit level understanding of immune cells and hematological cancers has been severely impeded by a lack of techniques that enable intracellular perturbation without significantly altering cell viability and function. Here, we demonstrate that vertical silicon nanowires (NWs) enable gene-specific manipulation of diverse murine and human immune cells with negligible toxicity. To illustrate the power of the technique, we then apply NW-mediated gene silencing to investigate the role of the Wnt signaling pathway in chronic lymphocytic leukemia (CLL). Remarkably, CLL-B cells from different patients exhibit tremendous heterogeneity in their response to the knockdown of a single gene, LEF1. This functional heterogeneity defines three distinct patient groups not discernible by conventional CLL cytogenetic markers and provides a prognostic indicator for patients' time to first therapy. Analyses of gene expression signatures associated with these functional patient subgroups reveal unique insights into the underlying molecular basis for disease heterogeneity. Overall, our findings suggest a functional classification that can potentially guide the selection of patient-specific therapies in CLL and highlight the opportunities for nanotechnology to drive biological inquiry.
authors.affiliation: Department of Chemistry, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Shalek
authors.forename: Jellert T
authors.initials: JT
authors.lastname: Gaublomme
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Nir
authors.initials: N
authors.lastname: Yosef
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chevrier
authors.forename: Mette S
authors.initials: MS
authors.lastname: Andersen
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Robinson
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pochet
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Rona S
authors.initials: RS
authors.lastname: Gertner
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.forename: Hongkun
authors.initials: H
authors.lastname: Park
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D051379:Mice; D053770:Nanowires / Q000737:chemistry* / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D012825:Silicon / Q000737:chemistry* / Q000633:toxicity
chemical_list: D051821:Lymphoid Enhancer-Binding Factor 1; D034741:RNA, Small Interfering; D012825:Silicon