Usted está aquí

Eventos

"IS DEMETHYLATION THE ONLY ROLE OF LYSINE SPECIFIC DEMETHYLASE 1 (LSD1)? THE FINDING OF A NOVEL PARADIGM ON EPIGENETIC THERAPIES"

"IS DEMETHYLATION THE ONLY ROLE OF LYSINE SPECIFIC DEMETHYLASE 1 (LSD1)? THE FINDING OF A NOVEL PARADIGM ON EPIGENETIC THERAPIES"

Fecha del evento: 
24/05/2018

Dr. Alba Maiques- Diaz

I am interested in understanding how epigenetic modifications and chromatin changes drive the leukemogenesis, with an emphasis on finding new targets or mechanisms to explore therapeutically.

I got my Biology Degree (2008) and my Master studies in Cell and Molecular Biology(2009) from U. Autonoma de Madrid. I got my PhD in 2014, working at the CNIO with Juan C Cigudosa and Sara Alvarez on the epigenetic changes induced by the fusion proteins AML1-ETO and MLL-AF9, frequent drivers of acute myeloid leukemia. I got an international mention and the 2013-2014 Excellence Award of the Faculty of Medicine (UAM) for my PhD thesis. During my PhD I published my work on Leukemia (Maiques-Diaz, 2012 Leukemia 26(6):1329-37) and in the British Journal of Haematology (Maiques-Diaz, 2016. Br J Haemtol 172(5):807-10), along with other collaborations (full list of publications can be found here). 

In 2014 I joined Tim C Somervaille group at the Cancer Research UK Manchester Institute, as a postdoctoral fellow. In Manchester I have been working on understanding the mechanisms of action of Lysine Specific Demethylase (LSD1/KDM1A) inhibitors currently in early phase clinical trials, a work that has been recently published in Cell Reports (Maiques-Diaz, 2018.  22(13): 3641-3659).

I am also the director of the North West area of the Society of the Spanish Researchers in the UK (SRUK/CERU) since Feb 2017, the co-founder of the Early Career Mentoring circles at CRUK-MI and the co-founder of the seisques project, created in 2016 to catalyse the use of creativity tools in the academic/research work.

Abstract

Acute myeloid leukaemia (AML) initiates when genetic aberrations occur in a hematopoietic stem/progenitor blood cell. These cause a blockage of their normal differentiation and an increase in their proliferation, leading to an accumulation of abnormal blood cells in the bone marrow. Chemotherapy is still the main line of treatment used, with broadly 20% of survival after 5 years. In this scenario, epigenetic factors, which are frequently found overexpressed or mutated in AML have emerged as promising candidate therapeutic targets.

One of those is the Lysine Specific Demethylase 1 (LSD1/KDM1A), frequently overexpressed in tumor types such as lung, prostate and haematological malignancies. LSD1 was identified as a core of the RCOR1 (CoREST) and histone deacetylase (HDAC) transcription corepressors complex and later found to have mono and di-methyl lysine 4 of histone H3 (H3K4me1/me2) specific demethylase activity, dependent on flavin adenine dinucleotide (FAD) cofactor. With several early phase clinical trials currently on going and appreciation of their mechanism of action was essential.

The assumption has been that the cell differentiation induced by LSD1 inhibitors was the result of the blockage of LSD1’s demethylase activity. However we found that treating AML cells with the LSD1 inhibitor OG86 (from Oryzon Genomics, Barcelona) induces differentiation by rapid changes in transcription without accumulation of the histone modifications targeted by LSD1 at sites of LSD1 binding. Moreover, a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as  the wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factors genes that regulate myeloid differentiation. The physical separation of LSD1/RCOR1 from GFI1 is required for differentiation and the consequent inactivation of GFI1 results in localised histone acetylation, increase enhancer activation and up regulation of subordinate, nearby genes (Maiques-Diaz, Cell Reports 2018).

AdjuntoTamaño
Icono PDF cartel_alba_maiques-diaz.pdf159.65 KB