Senthilkumar Ramamoorthy, PhD
Center for Pediatrics and Adolescent Medicine
A complex interplay between the epigenetic and transcriptional program of a cell in response to internal and external stimuli determines its fate. Using a combination of computational and experimental approaches, we aim to unravel the intersection of oncogenic signals, transcription factors and epigenetic regulators in the context of malignant transformation of hematopoietic cells, with a special focus on rare pediatric hematological malignancies (BMF, MDS and JMML).
Swetha Subramanian, PhD student
Sruthi Srinivasan, Master student
Epigenetics Response to Oncogenic Signaling in Hematological Malignancies
We are interested in understanding the epigenetic and transcription factors downstream of oncogenic signal transduction pathways. Epigenetic factors and the pioneering transcription factors determine cell fate. Oncogenic signaling exploits such fate determining factors and establishes a malignant epi-gene expression program. We are particularly interested in the RAS and JAK-STAT signaling associated epigenetic factor network in myeloid malignancies (JMML and MDS). A detailed understanding of aberrant signaling would provide insights into the process of malignant transformation and novel therapeutic approaches.
The Role of Cis-Regulatory Variants in The Development of Rare Hematological Malignancies
Functional non-coding elements (enhancers, repressors, insulators, boundary elements, LCR) play an important role in maintaining cell identity. We aim to identify and study such functionally important elements which are involved in maintaining normal and malignant hematopoiesis. We identify such elements in rare pediatric hematological malignancies using ChIPSeq, ATACSeq, Hi-C, etc. We will apply an integrative computational approach to identify such important regions. We will assess the functional significance of the identified regions by using the ncGeomeCRISPR editing method.
Therapy Induced Genomic Instability and DNA Damage Response
Improvements in therapeutic regimens for the treatment of childhood cancers have had a significant impact on survival rates. As a result of intensive chemotherapy and/or radiation therapy for the primary malignancy, an increasing number of survivors develop secondary complications. Therapy-related myeloid neoplasms (tMN), including MDS and acute myeloid leukemia (AML), are among the most devastating long-term sequelae. We aim to map the therapy-induced epigenetic and genomic alterations and underlying mechanisms that impact DNA repair response and genome stability.
Diagnostics for Pediatric Hematological Malignancies
We develop computational methods and diagnostic pipeline to identify and evaluate genes involved in the development of pediatric myeloid malignancies.
SELECTED RECENT PUBLICATIONS
Senthilkumar Ramamoorthy’s ORCID webpage can be found here: https://orcid.org/0000-0003-3468-4247
- Andreani V, Ramamoorthy S, Fassler R, Grosschedl R: Integrin beta1 regulates marginal zone B cell differentiation and PI3K signaling. Journal of Experimental Medicine 2023, 220.
- Roy R, Ramamoorthy S, Shapiro BD, Kaileh M, Hernandez D, Sarantopoulou D, Arepalli S, Boller S, Singh A, Bektas A, et al: DNA methylation signatures reveal that distinct combinations of transcription factors specify human immune cell epigenetic identity. Immunity 2021, 54:2465-2480 e2465.
- Derecka M, Herman JS, Cauchy P, Ramamoorthy S, Lupar E, Grun D, Grosschedl R: EBF1-deficient bone marrow stroma elicits persistent changes in HSC potential. Nature Immunology 2020, 21:261-273.
- Ramamoorthy S, Lebrecht D, Schanze D, Schanze I, Wieland I, Albert MH, Borkhardt A, Bresters D, Büchner J, Catala A, et al: NF1 Tumor Suppressor Gene Inactivation in Juvenile Myelomonocytic Leukemia: New Genetic Evidence and Consequences for Diagnostic Work-up. Blood 2020, 136:30-31. ASH 2020
- Ramamoorthy S, Kometani K, Herman JS, Bayer M, Boller S, Edwards-Hicks J, Ramachandran H, Li R, Klein-Geltink R, Pearce EL, et al: EBF1 and Pax5 safeguard leukemic transformation by limiting IL-7 signaling, Myc expression, and folate metabolism. Genes & Development 2020, 34:1503-1519.
- Boller S, Ramamoorthy S, Akbas D, Nechanitzky R, Burger L, Murr R, Schubeler D, Grosschedl R: Pioneering Activity of the C-Terminal Domain of EBF1 Shapes the Chromatin Landscape for B Cell Programming. Immunity 2016, 44:527-541.
Deutsche José Carreras Leukämie-Stiftung