Dissemin is shutting down on January 1st, 2025

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American Society of Hematology, Blood Advances, 23(5), p. 4864-4876, 2021

DOI: 10.1182/bloodadvances.2020003737

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Defining the transcriptional control of pediatric AML highlights RARA as a superenhancer-regulated druggable dependency

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Preprint: archiving forbidden
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Postprint: archiving forbidden
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Published version: archiving allowed
Data provided by SHERPA/RoMEO

Abstract

Abstract Somatic mutations are rare in pediatric acute myeloid leukemia (pAML), indicating that alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML samples, and MLL (KMT2A)–rearranged samples were also distinct from non–KMT2A-rearranged samples. Focusing specifically on superenhancers (SEs), we identified SEs associated with many known leukemia regulators. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort, and a RARA-associated SE was detected in 64% of the study cohort across all cytogenetic and molecular subtypes tested. RARA SE+ pAML cell lines and samples exhibited high RARA messenger RNA levels. These samples were specifically sensitive to the synthetic RARA agonist tamibarotene in vitro, with slowed proliferation, apoptosis induction, differentiation, and upregulated retinoid target gene expression, compared with RARA SE− samples. Tamibarotene prolonged survival and suppressed the leukemia burden of an RARA SE+ pAML patient-derived xenograft mouse model compared with a RARA SE− patient-derived xenograft. Our work shows that examining chromatin regulation can identify new, druggable dependencies in pAML and provides a rationale for a pediatric tamibarotene trial in children with RARA-high AML.