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.