Research in the Santos laboratory is focused on epigenetic regulation and transcription in normal and cancer cells, especially in Acute Myeloid Leukemia and B cell Lymphoma. Most recently the lab has been making novel discoveries uncovering the roles of both protein arginine methyltransferases and methyl-lysine readers on benign and malignant cell differentiation (Veazey et al., Leukemia, 2020; Van et al, JBC, 2022). The lab is also deeply invested in the understanding the function and regulation of the MLL3/4 complex in normal and malignant cells and is actively investigating the interplay of histone modifications and the DNA damage response. Ultimately the research in the Santos lab will define the mechanisms through which epigenetic regulation and transcription occur during normal differentiation and how these processes become disrupted in cancer, in order to develop specific and potent therapeutic strategies for treating cancer.
Other laboratory research interests include uncovering connections between replicative stress, epigenetic modifications, and DNA damage response and the epigenetic regulation of cancer stem cells. 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. Dr. Santos 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)
The Santos lab is exploring 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 the differentiation of leukemic stem cells is the next important step in designing new therapies against these cancers. The lab is also actively working on the epigenetic dys-regulation of leukemia stem cells, using models of AML. The lab is particularly focused on methylation of lysine and arginine histone residues, and has learned that inhibiting the arginine methyltransferase CARM1 reduces histone acetylase activity which leads to synthetic lethality in CREBBP/EP300-mutated lymphomas (Veazey et al., Leukemia, 2020), and that the histone methylation regulator PTIP is required for maintaining both normal and leukemic bone marrow niches (Das et al, PNAS, 2018).