Uckun Fatih M, Qazi Sanjive, Ma Hong, Yin Lichen, Cheng Jianjun
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027 ; Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027 ; Translational Oncology Program, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027.
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027 ; Bioinformatics Program, Gustavus Adolphus College, 800 W College Avenue, St. Peter, MN 56082.
EBioMedicine. 2014 Dec;1(2-3):141-155. doi: 10.1016/j.ebiom.2014.10.013.
The purpose of the present study was to further evaluate the biologic significance of the CD22ΔE12 molecular lesion and determine if it could serve as a molecular target for RNA interference (RNAi) therapy. We show that both pediatric and adult B-lineage lymphoid malignancies are characterized by a very high incidence of the CD22ΔE12 genetic defect. We provide unprecedented experimental evidence for a previously unrecognized causal link between CD22ΔE12 and aggressive biology of BPL cells by demonstrating that siRNA-mediated knockdown of CD22ΔE12 in primary BPL cells is associated with a marked inhibition of their clonogenicity. These findings provide the preclinical proof-of-concept that siRNA-mediated depletion of CD22ΔE12 may help develop effective treatments for high-risk and relapsed BPL patients who are in urgent need for therapeutic innovations. We also describe a unique polypeptide-based nanoparticle formulation of CD22ΔE12-siRNA as an RNAi therapeutic candidate targeting CD22ΔE12 that is capable of delivering its siRNA cargo into the cytoplasm of leukemia cells causing effective CD22ΔE12 depletion and marked inhibition of leukemic cell growth. Further development and optimization of this nanoparticle or other nanoformulation platforms for CD22ΔE12-siRNA may facilitate the development of an effective therapeutic RNAi strategy against paradigm shift in therapy of aggressive or chemotherapy-resistant B-lineage lymphoid malignancies.
本研究的目的是进一步评估CD22ΔE12分子病变的生物学意义，并确定其是否可作为RNA干扰（RNAi）治疗的分子靶点。我们发现，儿童和成人B系淋巴细胞恶性肿瘤的特征均为CD22ΔE12基因缺陷的高发生率。通过证明在原发性B系前体淋巴细胞（BPL）中，siRNA介导的CD22ΔE12敲低与它们克隆形成能力的显著抑制相关，我们为CD22ΔE12与BPL细胞侵袭性生物学之间先前未被认识的因果联系提供了前所未有的实验证据。这些发现提供了临床前概念验证，即siRNA介导的CD22ΔE12缺失可能有助于为迫切需要治疗创新的高危和复发BPL患者开发有效的治疗方法。我们还描述了一种独特的基于多肽的CD22ΔE12-siRNA纳米颗粒制剂，作为一种靶向CD22ΔE12的RNAi治疗候选物，它能够将其siRNA货物递送至白血病细胞的细胞质中，导致有效的CD22ΔE12缺失并显著抑制白血病细胞生长。这种纳米颗粒或其他用于CD22ΔE12-siRNA的纳米制剂平台的进一步开发和优化，可能有助于开发一种针对侵袭性或化疗耐药B系淋巴细胞恶性肿瘤治疗范式转变的有效的治疗性RNAi策略。
