According to a hierarchical model, targeting leukemia-initiating cells (LICs) was speculated to achieve complete remission (CR) or cure. Nonetheless, increasing evidence emphasized the plasticity of differentiated blasts undergoing interconversion into LICs. We exploited murine models of acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia driven by the promyelocytic leukemia/retinoic acid receptor (PML-RARα) oncofusion protein, which recruits histone deacetylase (HDAC)-containing complexes. We studied APLs with different LIC frequencies and investigated the effect of two HDAC inhibitors: valproic acid (VPA), with relative selectivity towards class I HDAC enzymes and vorinostat/suberoylanilide hydroxamic acid (SAHA) (pan-HDAC inhibitor) in combination with all-trans retinoic acid (ATRA), on the bulk APL cells and APL LICs. Indeed, we found that while VPA differentiates the bulk APL cells, SAHA selectively targets LICs. ATRA + VPA + SAHA combination efficiently induced CR in an APL model with lower LIC frequency. Substituting ATRA with synthetic retinoids as etretinate which promotes APL differentiation without downregulating PML/RARα compromised the therapeutic benefit of ATRA + VPA + SAHA regimen. Altogether, our study emphasizes the therapeutic power of co-targeting the plasticity and heterogeneity of cancer –herein demonstrated by tackling LICs and bulk leukemic blasts - to achieve and maintain CR.
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The RNA-Seq datasets generated in this study have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE196379.
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This study was supported by AIRC (AIRC IG20 grant to SaM), and was initially sponsored by CNR (Epigen Flagship Project). AKA has been granted a fellowship from Fondazione IEO-CCM.
The authors declare no competing interests.
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Moretti, S., Abdel-Aziz, A.K., Ceccacci, E. et al. Co-targeting leukemia-initiating cells and leukemia bulk leads to disease eradication. Leukemia 36, 1306–1312 (2022). https://doi.org/10.1038/s41375-022-01530-3
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