Identification and targeting of CD22ΔE12 as a molecular RNAi target to overcome drug resistance in high-risk B-lineage leukemias and lymphomas

Abstract

Aim: CD22ΔE12 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.

Methods: Gene 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.

Results: Leukemia 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.

Conclusion: The 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.

Keywords

Cancer / leukemia / RNA interference / nanomedicine / personalized medicine / driver lesion

References

[1] O'Leary M,Anderson JR.Progress in childhood cancer: 50 years of research collaboration, a report from the Children's Oncology Group..Semin Oncol2008;35:484-93 PMCID:PMC2702720

[2] Locatelli F,Bernardo ME.How I treat relapsed childhood acute lymphoblastic leukemia..Blood2012;120:2807-16

[3] Bhojwani D.Relapsed childhood acute lymphoblastic leukaemia..Lancet Oncol2013;14:e205-17

[4] Einsiedel HG,Hartmann R,Schrappe M,Mann G,Gobel U,Ludwig WD.Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia relapse study of the Berlin-Frankfurt-Munster Group 87..J Clin Oncol2005;23:7942-50

[5] Pui CH,Evans WE.Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?.Blood2012;120:1165-74 PMCID:PMC3418713

[6] Hogan LE,Yang J,Wong N,Condos G,Raetz E,Relling MV,Morrison DJ.Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies..Blood2011;118:5218-26 PMCID:PMC3217405

[7] Uckun FM,Ma H,Qazi S.CD22 Exon 12 deletion as a novel pathogenic mechanism of human B-precursor leukemia..Proc Natl Acad Sci U S A2010;107:16852-7 PMCID:PMC2947921

[8] Ma H,Ozer Z,Reaman GH.CD22 Exon 12 deletion is a characteristic genetic defect of therapy-refractory clones in paediatric acute lymphoblastic leukaemia..Br J Haematol2012;156:89-98

[9] Uckun FM,Ma H,Mitchell LG.CD22ΔE12 as a molecular target for corrective repair using RNA trans-splicing: anti-leukemic activity of a rationally designed RNA trans-splicing molecule..Integr Biol (Camb)2015;7:237-49 PMCID:PMC4373651

[10] Uckun FM,Ma H,Cheng J.A rationally designed nanoparticle for RNA interference therapy in B-lineage lymphoid malignancies..EBioMedicine2014;1:141-55 PMCID:PMC4292938

[11] Uckun FM,Cheng J,Qazi S.CD22ΔE12 as a molecular target for RNAi therapy..Br J Haematol2015;169:401-14 PMCID:PMC4486322

[12] Den Boer ML,De Menezes RX,Buijs-Gladdines JG,Van Zutven LJ,Van der Spek PJ,Horstmann MA,Kamps WA,Pieters R.A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study..Lancet Oncol2009;10:125-34

[13] van der Veer A,Pieters R,Van Reijmersdal SV,Harrison CJ,van der Velden VH,Van Leeuwen F,Horstmann MA,Rizopoulos D,Sonneveld E,Den Boer ML.Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL..Blood2013;122:2622-9 PMCID:PMC3795461

[14] Uckun FM,Cheng J.Targeting leukemic stem cells with multifunctional bioactive polypeptide nanoparticles..Future Oncol2015;11:1149-52

[15] Zheng N,Liu Y,Zhang R,Uckun FM,Cheng J.Redox-responsive, reversibly-crosslinked thiolated cationic helical polypeptides for efficient siRNA encapsulation and delivery..J Control Release2015;205:231-9

[16] He H,Song Z,Yao C,Zhang C,Uckun FM,Zhang Y.Suppression of hepatic inflammation via systemic siRNA delivery by membrane-disruptive and endosomolytic helical polypeptide hybrid nanoparticles..ACS Nano2016;10:1859-70

[17] Uckun FM,Qazi S,Zheng N,Song Z,Cheng J.Development of polypeptide-based nanoparticles for non-viral delivery of CD22 RNA trans-splicing molecule as a new precision medicine candidate against B-lineage ALL..E Bio Medicine2015;2:649-59 PMCID:PMC4534679

[18] D'Cruz OJ.Novel monoclonal antibody-based therapies for leukemia..In: Monoclonal Antibodies in Oncology.2013;LondonFuture Medicine Ltd54-77

[19] Uckun FM,Qazi S,Ozer Z.Recombinant human CD19-ligand protein as a potent anti-leukemic agent..Br J Haematol2011;153:15-23

[20] Uckun FM,Qazi S,Rose R,Ma H.Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia..J Clin Invest2015;125:1006-18 PMCID:PMC4362237

[21] Uckun FM.Recombinant human CD19 ligand for biotherapy of B-lineage lymphoid malignancies..J Nanomed Biotherapeut Discov2012;2:e117