title: CD22ΔE12 as a molecular target for RNAi therapy.
abstract: B-precursor acute lymphoblastic leukaemia (BPL) is the most common form of cancer in children and adolescents. Our recent studies have demonstrated that CD22ΔE12 is a characteristic genetic defect of therapy-refractory clones in paediatric BPL and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory paediatric BPL. The purpose of the present study is to evaluate the biological significance of the CD22ΔE12 molecular lesion in BPL and determine if it could serve as a molecular target for RNA interference (RNAi) therapy. Here we report a previously unrecognized causal link between CD22ΔE12 and aggressive biology of human BPL cells by demonstrating that siRNA-mediated knockdown of CD22ΔE12 in primary leukaemic B-cell precursors is associated with a marked inhibition of their clonogenicity. Additionally, we report a nanoscale liposomal formulation of CD22ΔE12-specific siRNA with potent in vitro and in vivo anti-leukaemic activity against primary human BPL cells as a first-in-class RNAi therapeutic candidate targeting CD22ΔE12.
authors: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA, USA; Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA, USA; Translational and Clinical Sciences Program, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA, USA.
authors: Fatih M
authors: FM
authors: Uckun
authors: Hong
authors: H
authors: Ma
authors: Jianjun
authors: J
authors: Cheng
authors: Dorothea E
authors: DE
authors: Myers
authors: Sanjive
authors: S
authors: Qazi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes; D051379:Mice; D008822:Mice, Transgenic; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051918:Sialic Acid Binding Ig-like Lectin 2
keywords: acute leukaemia; childhood haematological malignancies; experimental therapies; molecular pathogenesis; new drugs for leukaemia