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Please use this identifier to cite or link to this item: http://hdl.handle.net/11375/32263
Title: INVESTIGATION OF THE COMBINATION EFFECT OF LSD1 INHIBITION WITH THE NOVEL RARα AGONIST TAMIBAROTENE
Other Titles: LSD1 INHIBITION AND TAMIBAROTENE
Authors: Coopersmith, Sarah
Advisor: Berg, Tobias
Department: Biochemistry and Biomedical Sciences
Keywords: Acute Myeloid Leukaemia;ATRA;Tamibarotene;Bomedemstat;Cancer;Hematopoiesis;Bone Marrow;RARA;Super-enhancer;Epigenetics;Retinoids;Retinoic Acid
Publication Date: 2025
Abstract: Acute Myeloid Leukemia (AML) is an aggressive cancer caused by mutations that prevent cell differentiation. All-trans retinoic acid (ATRA), a retinoic acid receptor alpha (RARα) agonist, effectively treats acute promyelocytic leukemia (APL), but its effectiveness is limited in non-APL AML. LSD1 (lysine-specific histone demethylase 1) is often upregulated in AML and inhibiting it (LSD1i) enhances ATRA-induced differentiation in ATRA-sensitive non-APL subtypes. Tamibarotene, a more potent RARα agonist, has shown improved efficacy over ATRA in non-APL AML models with high RARA expression. We explored whether Tamibarotene is a better partner for LSD1i and whether LSD1i could increase RARA expression, shifting cells from RARA-low to RARA-high. Two RARA-high cell lines (OCI-AML3 and MV4-11) and two RARA-low lines (Kasumi-1 and KG-1a) were used to study the effects of ATRA, Tamibarotene, and Bomedemstat on differentiation, cell viability, and gene expression. We examined their responses to ATRA, Tamibarotene, and the LSD1 inhibitor Bomedemstat, alone and in combination. Both combinations in RARA-high cells showed synergistic antiproliferative effects, but neither was clearly superior. Neither ATRA nor Tamibarotene showed synergy with Bomedemstat in RARA-low cells. RARA-high cells underwent differentiation when treated with ATRA and Bomedemstat, and Tamibarotene and Bomedemstat, evidenced by increased levels of CD86 and CD11b (markers of mature differentiation) and decreased CD14 (a monocytic marker). No additive changes in differentiation markers were observed in RARA-low cells. Gene expression analysis revealed that LSD1i did not shift cellular RARA expression from low to high; after treatment with LSD1i, RARA levels remained significantly different between RARA-low and RARA-high cells. In conclusion, RARα agonists synergize with LSD1i in RARA-high cells, with no significant difference between ATRA and Tamibarotene. Bomedemstat showed activity as a monotherapy in some RARA-low cells but was not synergistic with RARα agonists, indicating that the success of combination therapy may depend on baseline RARA expression levels.
URI: http://hdl.handle.net/11375/32263
Appears in Collections:Open Access Dissertations and Theses

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