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Abstract Acute myeloid leukemia (AML) remains a challenging disease with a poor prognosis, necessitating more personalized therapeutic strategies. Retinoic acid receptor (RAR) activation is crucial for myeloid differentiation, but non-APL AML cells resist differentiation induced by the pan-RAR agonist all-trans retinoic acid (ATRA). Am80, a specific RARA agonist, has been reported to partially overcome this resistance in AML with high RARA expression. However, its effects on myeloid differentiation, especially in comparison to ATRA, remain understudied. We compared the effects of Am80 and ATRA in non-APL AML samples, focusing on subsets with high RARA and/or RARG expression, using molecular and phenotypic differentiation assessments. Contrary to previous findings, high RARA levels alone did not foster myeloid differentiation upon Am80 treatment in primary AML. At cellular and molecular levels, Am80 and ATRA induced identical molecular and differentiation responses. Nevertheless, combined treatment of both retinoids with LSD1 and GCN5 inhibitors efficiently unlocked differentiation in various types of non-APL AML, particularly in those with higher RARA levels. Our findings highlight the potential of Am80 in the field of personalized AML treatment, particularly when utilized in conjunction with epigenetic modifiers in RARA-high AML, warranting further clinical investigation.
Schenk et al. (Tue,) studied this question.