The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. Treatment of AML cells with LSD1 inhibitors shows a highly variable pattern of response and only a minority of AML cells are sensitive to LSD1 inhibition as single treatment. However, a strong cooperation of LSD1 inhbition and the differentiation agent retinoic acid (RA) can be observed in most of the AML subtypes, even in those resistant to either drug alone. In acute promyelocytic leukemia (APL), pharmacological doses of RA induce differentiation of APL cells through degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knock-out, but LSD1 inhibition sensitizes them to physiological doses of RA without altering the stability of PML-RAR, and extends survival of leukemic mice upon RA treatment. Non-enzymatic activities of LSD1 are essential to block differentiation of leukemic cells, while the combination of LSD1 inhibitors (or LSD1 knock-out) with low doses of RA releases a differentiation-associated gene expression program, not strictly dependent on changes in histone H3K4 methylation (known substrate of LSD1). An integrated proteomic/epigenomic/mutational analysis showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin through inhibition of the interaction between LSD1 and GFI1, a relevant transcription factor in hematopoiesis. Same experiments performed in non-APL AML cells confirmed the critical role of LSD1-GFI1 interaction in RA sensitization, beside the APL context.
|Titolo:||DISSECTING THE ROLE OF LSD1 IN THE RESPONSE OF ACUTE MYELOID LEUKEMIA CELLS TO RETINOIC ACID TREATMENT|
|Supervisori e coordinatori interni:||MINUCCI, SAVERIO|
|Data di pubblicazione:||28-gen-2020|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Citazione:||DISSECTING THE ROLE OF LSD1 IN THE RESPONSE OF ACUTE MYELOID LEUKEMIA CELLS TO RETINOIC ACID TREATMENT / R. Ravasio ; internal advisor: D. Pasini ; external advisor: G. Gargiulo. - Milano : Università degli studi di Milano. DIPARTIMENTO DI BIOSCIENZE, 2020 Jan 28. ((31. ciclo, Anno Accademico 2019.|
|Appare nelle tipologie:||Tesi di dottorato|