Targeting leukemic stem cells in a murine model of CALM-AF10 positive acute myeloid leukemia

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We show that the leukemic LSC clone in the CALM-AF10 leukemia mouse model B220+Mac1- can be regenerated by B220+Mac1+ subpopulation in transplanted mice. In vivo experiments showed that the B220+Mac1+ cells could give rise to the B220+Mac1- cell compartment enriched in LSC activity, showing similar immuno-phenotype to the B220+Mac1- LSC compartment in primary and secondary transplanted leukemic mice with regard to B220 and Mac1 expression. Interestingly, though both of the leukemias generated by bulk and B220+Mac1+ cells transplant had similar immuno-phenotypes, they showed distinct gene expression patterns among the three subpopulations. The B220+Mac1- population showed gene set enrichment for LSC and ESC gene sets in line with their high enrichment for LSC activity compared to the other populations. Common pathways between differentially expressed genes of B220+Mac1- versus B220+Mac1+ and B220+Mac1- versus B220-Mac1+; identified using in silco approaches, cumulative comparisons of protein interactions, gene ontology and pathway enrichment analyses identified Nod and Toll-like receptor signaling pathways, cytokine-cytokine receptor interaction and chemokine signaling pathway, which could be used for development of novel targeted approaches. Initial results showed that the clonogenicity of B220+Mac1- and B220+Mac1+ subpopulations can be targeted by commonly used pathway inhibitory drugs like gefitinib. Here we could successfully demonstrate that targeting of LSCs using a novel approach of loading daunorubicin in biocompatible antibody conjugated mesoporous silica nanoparticles, is accompanied by better selectivity, target-ability, efficacy and specificity than the drug alone. These anti-B220 MSN DN particles have promising properties for selective and efficient drug delivery to the target cells in vitro by passive uptake of daunorubicin at the cell surface. Using this approach, we also showed significant higher toxicity of anti-B220 MSN DN on B220+ CALM-AF10 ex vivo cells compared to the negative control, B220- Cdx2 ex vivo cells, indicating target specificity of these conjugated MSN to B220+ cells. Transplantation in mice after prior treatment of LSCs with anti-B220 MSN DN caused delay in leukemia development. These data demonstrate that it is feasible to tag MSNs with specific antibodies which can target the LSCs with reduced toxicity towards other cells.

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