Department of Hematology
Erasmus Cancer Institute
PhD Thesis Roger Mulet-Lázaro
Thank you for your interest in my thesis. Here you will find the entire book available for download, as well as links to the publications included in the thesis. Supplementary tables of both published and unpublished chapters are also available here.
You can download the entire thesis in PDF format here.
Epigenetic mechanisms lie at the heart of hematopoiesis, precisely establishing the transcriptional program of blood cells along the differentiation continuum. Disruptions in these mechanisms often give rise to dysregulation of genes critically involved in proliferation or differentiation, ultimately resulting in leukemia. In fact, almost 75% of AML patients carry mutations in epigenetic modifiers. Our understanding of epigenetics has come a long way since the early days when Waddington proposed his famous model of valleys and ridges, which are no longer seen as theoretical constructs, but measurable features such as DNA methylation, histone acetylation and transcription factor binding. The addition of next generation sequencing (NGS) technologies to the arsenal of the molecular biologist has made it possible to chart the epigenetic landscape of entire genomes, even in single cells. Nevertheless, this unprecedented wealth of data has come with its own unique set of challenges, namely in terms of data analysis and interpretation -- bioinformatics has emerged as an indispensable discipline to face these challenges.
The work presented in this thesis draws from molecular biology and bioinformatics alike to shed light on the epigenetic mechanisms on both healthy and malignant hematopoiesis. The thesis comprises three main research lines: (1) epigenetic mechanisms in healthy hematopoiesis, (2) enhancer hijacking in AML with 3q26 rearrangements, and (3) epigenetic changes in cis-regulatory elements driving altered gene expression
Chapter 2: Induced cell-autonomous neutropenia systemically pertstyleurbs hematopoiesis in Cebpa enhancer-null mice (Blood Advances, 2021)
Chapter 3: Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia (Blood, 2020)
Chapter 4: The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops (Nature Communications, 2021)
- Read the paper here.
- Download the Supplementary Information here.
- Download the Supplementary Data (containing primers names and sequences) here.
Chapter 5: Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia (Cancer Discovery, 2021)
Chapter 6: Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML (Blood, 2021)
- Read the paper here.
- Download the Supplementary Tables: Table S1, Table S2, Table S3, Table S4, Table S5, Table S6.
Chapter 7: Integrated analysis of the epigenetic landscape of mixed myeloid/lymphoid leukemias (Work in progress)
- Download the Supplementary Tables here.
