Assistant Professor, Department of Epigenetics and Molecular Carcinogenesis, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX
Faculty Member, Graduate School of Biomedical Sciences (GSBS), The University of Texas Health Science Center, Houston, TX
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.
|2007||University of Lisbon Medical School and Gulbenkian Institute, Lisbon, PRT, PHD, Biomedical Sciences-Immunology|
|1999||University of Lisbon School of Sciences, Lisbon, PRT, BS, MS, Molecular Biology and Genetics|
|2008-2015||Postdoctoral Fellow, Genome Integrity, NIH, Bethesda, MD|
|2007-2008||Visiting Fellow, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA|
|2017||Basic/Translational Junior Faculty, American Society of Hematology (ASH)|
|2016||Kimmel Scholar Award, Sidney Kimmel Foundation|
|2015||First Time, Tenure-Track Faculty Recruitment Award, Cancer Prevention and Research Institute of Texas (CPRIT)|
|2015||New Faculty Award, Cancer Center Support Grant (CCSG), NCI|
- Kaushik S, Liu F, Veazey KJ, Gao G, Das P, Neves LF, Lin K, Zhong Y, Lu Y, Giuliani V, Bedford MT, Nimer SD, Santos MA. Genetic deletion or small molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia 32(2):499-509, 2018. e-Pub 2017. PMID: 28663579.
- Starnes LM, Su D, Pikkupeura LM, Weinert BT, Santos MA, Mund A, Soria R, Cho YW, Pozdnyakova I, Kubec Højfeldt M, Vala A, Yang W, López-Méndez B, Lee JE, Peng W, Yuan J, Ge K, Montoya G, Nussenzweig A, Choudhary C, Daniel JA. A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex. Genes Dev 30(2):149-63, 2016. e-Pub 2016. PMID: 26744420.
- Santos MA, Faryabi RB, Ergen AV, Day AM, Malhowski A, Canela A, Onozawa M, Lee JE, Callen E, Gutierrez-Martinez P, Chen HT, Wong N, Finkel N, Deshpande A, Sharrow S, Rossi DJ, Ito K, Ge K, Aplan PD, Armstrong SA, Nussenzweig A. DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier. Nature 514(7520):107-11, 2014. e-Pub 2014. PMID: 25079327.
- Callen E, Di Virgilio M, Kruhlak MJ, Nieto-Soler M, Wong N, Chen HT, Faryabi RB, Polato F, Santos M, Starnes LM, Wesemann DR, Lee JE, Tubbs A, Sleckman BP, Daniel JA, Ge K, Alt FW, Fernandez-Capetillo O, Nussenzweig MC, Nussenzweig A. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 153(6):1266-80, 2013. e-Pub 2013. PMID: 23727112.
- Daniel JA, Santos MA, Wang Z, Zang C, Schwab KR, Jankovic M, Filsuf D, Chen HT, Gazumyan A, Yamane A, Cho YW, Sun HW, Ge K, Peng W, Nussenzweig MC, Casellas R, Dressler GR, Zhao K, Nussenzweig A. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science 329(5994):917-23, 2010. e-Pub 2010. PMID: 20671152.
- Santos MA, Huen MS, Jankovic M, Chen HT, López-Contreras AJ, Klein IA, Wong N, Barbancho JL, Fernandez-Capetillo O, Nussenzweig MC, Chen J, Nussenzweig A. Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8. J Exp Med 207(5):973-81, 2010. e-Pub 2010. PMID: 20385748.
- Santos MA, Sarmento LM, Rebelo M, Doce AA, Maillard I, Dumortier A, Neves H, Radtke F, Pear WS, Parreira L, Demengeot J. Notch1 engagement by Delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells. Proc Natl Acad Sci U S A 104(39):15454-9, 2007. e-Pub 2007. PMID: 17878313.
- Santos MA, John S, Nussenzweig A. Tumor promoting role of the DNA damage response. Cell Cycle 13(18):2807-8, 2014. PMID: 25486465.
|Title:||Recruitment of First-time, Tenure-Track Faculty - Dr. Margarida Santos|
|Funding Source:||Cancer Prevention & Research Institute of Texas (CPRIT)|
|Title:||Targeting Protein Arginine Methylation in MLL-fusion AML|
|Funding Source:||Sidney Kimmel Foundation-Kimmel Scholar Award|