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ACUTE MYELOID LEUKEMIA

Co-targeting leukemia-initiating cells and leukemia bulk leads to disease eradication

Leukemia volume 36, pages 1306–1312 (2022)Cite this article

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Abstract

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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Fig. 1: Vorinostat/suberoylanilide hydroxamic acid (SAHA) treatment reduces leukemia-initiating cells (LIC) frequency in APL mice.
Fig. 2: Combined treatment with suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA) and all-trans retinoic acid (ATRA) triggers leukemia-initiating cell (LIC) clearance and cures leukemic mice.
Fig. 3: Rationale co-targeting of leukemic stem cells (LSC) and bulk leukemic blasts yields superior therapeutic efficacy.

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Data availability

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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Funding

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.

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Author notes

  1. These authors contributed equally: Simona Moretti, Amal Kamal Abdel-Aziz.

Authors and Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy

    Simona Moretti, Amal Kamal Abdel-Aziz, Elena Ceccacci, Isabella Pallavicini, Fabio Santoro & Saverio Minucci

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

    Amal Kamal Abdel-Aziz

  3. Institut de Recherche Saint-Louis (IRSL), Université de Paris, INSERM U944/CNRS UMR7212, Paris, France

    Hugues de Thé

  4. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Saverio Minucci

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  1. Simona Moretti
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  3. Elena Ceccacci
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Contributions

SaM conceived the work. SM designed and performed experiments, analyzed and discussed results. AKA and EC performed bioinformatic analysis. AKA, FS and IP performed experiments, analyzed results and discussed results. HdT discussed results. SaM designed experiments, supervised the entire study, provided intellectual and technical support. SM, AKA, HdT and SaM contributed to manuscript writing and editing.

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Correspondence to Saverio Minucci.

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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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