Abstract
AimCD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia (BPL) cells. The purpose of the present study was to identify the CD22ΔE12-specific signature transcriptome in human BPL cells and evaluate the clinical potential of a nanoscale formulation of CD22ΔE12-siRNA as an RNAi therapeutic against drug-resistant BPL. CD22ΔE12-siRNA nanoparticles significantly improved the event-free survival (EFS) outcome of NOD/SCID (NS) mice challenged with human BPL xenograft cells.MethodsGene expression and translational bioinformatics methods were applied to examine the expression of the CD22ΔE12-specific signature transcriptome in human BPL cells in subsets of BPL patients. Survival analysis for mice challenged with BPL cells and treated with CD22ΔE12 siRNA was performed using standard methods.ResultsLeukemia cells from CD22ΔE12-Tg mice exhibit gene and protein expression profiles consistent with constitutive activation of multiple signaling networks, mimicking the profiles of relapsed BPL patients as well as newly diagnosed high-risk patients with BCR-ABL+/Philadelphia chromosome (Ph)+ BPL as well as Ph-like BPL. A nanoscale formulation of CD22ΔE12-siRNA abrogated the in vivo clonogenicity of the leukemia-initiating leukemic cell fraction in xenograft specimens derived from patients with relapsed BPL and significantly improved the EFS outcome of NS mice challenged with drug-resistant human BPL xenograft cells.ConclusionThe CD22-RNAi technology is applicable to all BPL patients both high risk and standard risk. That is because CD22ΔE12 is a characteristic feature of drug-resistant leukemic clones that escape chemotherapy and cause relapse in both high risk and low risk subgroups of patients. The technology therefore has the potential (1) for prevention of relapses by selectively killing the clones that are most likely to escape chemotherapy and cause relapse as well (2) for treatment of relapses in BPL. This research project may also lead to innovative salvage regimens against other forms of CD22ΔE12-positive relapsed B-lineage leukemias and lymphomas.
Highlights
B-precursor acute lymphoblastic leukemia (BPL) is the most common form of cancer in children and adolescents and a leading cause of cancer-related mortality in children[1,2,3,4,5]
The CD22-RNAi technology is applicable to all BPL patients both high risk and standard risk
CD22ΔE12 is a driver lesion that we recently identified as the likely genetic cause for the drug resistance-associated activation of mitogenactivated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K)/m-TOR and WNT pathways in primary leukemia cells from relapsed as well as newly diagnosed high-risk BPL patients[7,8]
Summary
B-precursor acute lymphoblastic leukemia (BPL) is the most common form of cancer in children and adolescents and a leading cause of cancer-related mortality in children[1,2,3,4,5]. Hogan et al.[6] reported the results of an integrated genomic analysis of primary leukemia cells from relapsed BPL patients, which showed that relapse clones are characterized by concomitant activation of mitogenactivated protein kinase (MAPK) and WNT pathways - but the driver lesion that causes this distinct gene expression signature has remained elusive. Both pathways have been implicated in chemotherapy resistance and aggressiveness of BPL cells. Our studies using quantitative real time RT-PCR on samples obtained from 114 newly diagnosed pediatric ALL patients showed a high incidence of CD22ΔE12 in pediatric BPL and confirmed the presence of this genetic defect in 100% (14/14) of infant ALL cases[7,8,9,10,11]
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