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Background <p>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 (tamibarotene), 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.</p> Methods <p>In this study 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.</p> Results <p>In contrast to previous findings, Am80 showed no advantage over ATRA in inducing differentiation in AML cell lines or primary samples, regardless of RARA and RARG expression levels. Cotreatment with inhibitors of the epigenetic modifiers LSD1 and GCN5, which facilitates retinoid-induced myeloid differentiation, enhanced the effects of both Am80 and ATRA to the same extent, with more pronounced responses observed in RARA-high samples. Gene expression analysis revealed identical molecular responses to Am80 and ATRA.</p> Conclusions <p>The study provides evidence that ATRA can be substituted by the more stable Am80 in retinoid-based AML therapies. It also identifies elevated RARA expression as a potential marker for sensitivity to combination therapy with retinoids and epigenetic inhibitors in AML.</p>

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Am80 (tamibarotene) and ATRA induce highly similar molecular responses and myeloid differentiation in non-APL AML, enhanced by LSD1/GCN5 inhibition and increased RARA expression

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  • 出版模式：

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  • 发表日期：

    2026年6月27日

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  • Faezeh Ghazvini Zadegan,
  • Clara Stanko,
  • Franziska Fiedler,
  • Laura Ölsner,
  • Setenay Gupse Özcan,
  • Jacqueline Schütt,
  • Tina M. Schnöder,
  • Yordan Sbirkov,
  • Lukasz Szymanski,
  • Sven Stengel,
  • Peter Dittrich,
  • Jörg P. Müller,
  • Florian H. Heidel,
  • Andreas Hochhaus,
  • Sebastian Scholl,
  • Ulf Schnetzke,
  • Annamaria Brioli,
  • Tino Schenk

摘要

Background

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 (tamibarotene), 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.

Methods

In this study 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.

Results

In contrast to previous findings, Am80 showed no advantage over ATRA in inducing differentiation in AML cell lines or primary samples, regardless of RARA and RARG expression levels. Cotreatment with inhibitors of the epigenetic modifiers LSD1 and GCN5, which facilitates retinoid-induced myeloid differentiation, enhanced the effects of both Am80 and ATRA to the same extent, with more pronounced responses observed in RARA-high samples. Gene expression analysis revealed identical molecular responses to Am80 and ATRA.

Conclusions

The study provides evidence that ATRA can be substituted by the more stable Am80 in retinoid-based AML therapies. It also identifies elevated RARA expression as a potential marker for sensitivity to combination therapy with retinoids and epigenetic inhibitors in AML.