Dr. Margarida I. Albuquerque Almeida Santos
The University of Texas MD Anderson Cancer Center
Department of Epigenetics and Molecular Carcinogenesis
My scientific interests are focused on replicative stress/DNA damage response and epigenetic regulators in stem cell cancer. Current studies in my laboratory focus on the hematopoietic system, since 1) it is a well-established system for adult stem cells studies and 2) the dynamic nature of the hematopoietic system places it in a vulnerable position with respect to genomic damage during DNA replication. Replicative stress can be defined as a slowing or stalling of replication fork progression and a source of spontaneous DNA lesions that drives genomic instability. “Oncogene-induced” replicative stress is a major driving force of hematological cancers. Aberrant oncogene expression induces precocious entry into S phase and perturbs replication fork progression, triggering the DNA damage response. The classical view of the DNA damage response (DDR) postulates that DDR is a crucial tumorigenesis barrier in early stages of cancer development, and a selective pressure that favors malignant clones with defects in DNA repair factors. My recent work showed that DNA damage induces the differentiation of leukemic stem-like cells in acute myeloid leukemia (AML) harboring the MLL-AF9 oncogene, thus uncovering an unexpected tumor-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in AML (Santos et al., Nature 2014).
Current studies in my laboratory explore the concept of “DNA damage-induced differentiation of stem-like cancer cells” in AML and other aggressive hematological malignancies using mouse models, next generation sequencing and various DNA damage treatments and assays. Elucidating which DNA damage response proteins should be targeted in order to promote effective differentiation of leukemic stem cells is the next important step in designing new therapies against these cancers.
A tutorial with us would provide experience in mouse work (in vivo leukemia studies), flow cytometry, next generation sequencing (ChIp-seq, RNA-seq and exome sequencing), immunofluorescence and cytology.