The Santos laboratory’s scientific interests are focused on replicative stress/DNA damage response and epigenetic regulation of cancer stem cells. Current studies in the Santos laboratory focus on the hematopoietic system for two reasons: first, it is a well-established system for adult stem cells studies; and second, the dynamic nature of the hematopoietic system makes it vulnerable to genomic damage occurring during DNA replication. Replicative stress which can stem from the slowing or stalling of replication fork progression, is a source of spontaneous DNA damage 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 it is a crucial barrier to tumorigenesis during the early stages of cancer development, and that selective pressure favors malignant clones with defects in DNA repair factors, or genome guardians. Acute leukemias are typified by the accumulation of immature blood cells, or blasts, that are not fully differentiated. We recently showed that DNA damage induces the differentiation of leukemic stem-like cells in acute myeloid leukemia (AML) harboring the MLL-AF9 oncogene. This discovery uncovered an unexpected tumor-promoting role of the genome guardians in enforcing the oncogene-induced differentiation blockade in AML (Santos et al., Nature, 2014)
Currently my lab is exploring the concept of DNA damage-induced differentiation of stem-like cancer cells in AML and other aggressive hematological malignancies. We use 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 the differentiation of leukemic stem cells is the next important step in designing new therapies against these cancers. We are also actively working on the epigenetic dys-regulation of leukemia stem cells, using our models of AML. We are particularly focused on methylation of lysine and arginine histone residues, and we have learned that inhibiting the arginine methyltransferase CARM1 reduces histone acetylase activity which leads to synthetic lethality in CREBBP/EP300-mutated lymphomas (Veazey et al, 2020), and that the histone methylation regulator PTIP is required for maintaining both normal and leukemic bone marrow niches (Das et al, 2018).