Bio sketch Dr. Tata Nageswara Rao
Dr. Tata Nageswara Rao received his PhD from the University of Ulm, Germany. During his doctoral studies in Dr. Hans Joerg Fehling’s laboratory, Dr. Rao conducted in vivo lineage tracing studies to identify T-lymphocyte competent hematopoietic stem and progenitor cells. To continue to stoke his keen interest in hematopoietic stem cells, metabolism and aging research, in 2011, Dr. Rao moved to Boston to pursue his post-doctoral training in Dr. Amy Wagers laboratory, Harvard University and Harvard Medical School. In 2015, Dr. Rao returned to Europe and joined the Department of Biomedicine, University Hospital Basel and University of Basel as a project leader (mentor: Dr. Radek Skoda). He investigated stem cell and metabolic aspects of myeloproliferative neoplasms to identify metabolic dependencies of leukemic stem cells. In 2020, Dr. Rao joined the faculty of medicine, University Clinic of Hematology, Bern University Hospital, and established his independent laboratory - Stem cells, Leukemia, Aging and Metabolism Laboratory (SLAM Lab) at the Department for BioMedical Research (DBMR), University of Bern (Mentor: Dr. Anne Angelillo-Scherrer). Dr. Rao is a member of the European Hematology Association (EHA) and American Society of Hematology (ASH).
Contribution to science
Dr. Rao research has been focused at the interface of hematopoietic stem cell (HSC) biology and blood cancers to elucidate cellular and molecular pathways regulating functional maintenance and lineage fate choices of HSCs in health, aging, and hematologic malignancies. During his doctoral studies Dr. Rao conducted in vivo lineage tracing studies by generating and analyzing knock-in mouse models (pTα/Cre-knock-in mice (Luche H and Rao TN, et al., J.Ex.Med, 2013) and Gata3/YFP knock-in mice (Rao TN et., J.Immunol, 2019) for in vivo lineage tracing of T-lymphocytes competent hematopoietic stem and progenitor cells (HSPCs). Meanwhile, Gata3/YFP knock-in mice have become a most useful tool to identify cells of the T- and innate lymphoid cell type 2 lineages and their precursors (Li BWS et al., Front. Immuno. 2017; Stadhouders T et al., Allergy Clin. Immunol. 2018).
During his post-doctoral training, Dr. Rao pursued multiple independent projects including important work on the roles of the Gpr56, Lin28, Protein kinase Cδ (PKCδ), and transcription factor Egr1 in HSCs and hematopoiesis. His investigations i). identified Gpr56 is a novel marker of primitive HSCs in the bone marrow and also provided definitive evidence that Gpr56 is dispensable for the function of adult HSCs (Rao TN et al., Stem Cell Res, 2015); ii). identified that the RNA binding protein Lin28 acts as a critical regulator of myeloid cell development and mastcytosis (Wang LD* and Rao TN* et al., Leukemia, 2015); iii). uncovered a novel role for PKCδ, a serine/threonine kinase in regulating HSPC pool size, fitness and metabolic activity, thereby identifying PKCδ signaling as a critical rheostat of HSPC expansion. His efforts further identified PKCδ as a common upstream regulator that may coordinate the activities of multiple targets implicated in HSPC homeostasis. These findings suggest the potential therapeutic relevance of PKCδ as a new target to expand HSPCs for regenerative medicine purposes (Rao TN et al., EMBO, 2018).
Over the course of his scientific journey, Dr. Rao has become intrigued by the concept that normal hematopoiesis and leukemogenesis may be distorted mirror images, and that studying the mechanisms of normal hematopoiesis is instrumental to understand and target hematologic malignancies. Motivated by this concept, Dr. Rao investigated the lineage fate choices and metabolic dependencies of normal and leukemic HSPCs. His studies identified various altered metabolic nodes in MPN propagating HSPCs, and demonstrated the therapeutic relevance of targeting altered glucose metabolism in MPNs (Rao TN et al., Blood, 2019). In parallel, he also explored the cellular and functional heterogeneity in primitive HSPCs and its functional relevance to the MPN pathogenesis (Rao TN et al., Blood, 2021). Dr. Rao serves as an ad-hoc reviewer for key journals in the field (Blood, Blood Advances, Leukemia, Cell Stem Cell, J Ex Med, and Nature Genetics).
Major achievements of the last 5 years
Dr. Rao received a Translational Research Training in Hematology (TRTH) fellowship from the EHA-ASH society (2017), and a career transition fellowship from the University of Basel (2017). For his work on elucidating the role of metabolic reprogramming in the pathogenesis of myeloproliferative neoplasms (MPNs) and for his investigations on deciphering leukemic HSC functional heterogeneity and lineage fate choices, he received ‘outstanding experimental hematologist awards from the Swiss Society of Oncology and Hematology’ in 2018 and 2019. In 2019, Dr. Rao received a Swiss National Science Foundation (SNF) grant. In 2020, Dr. Rao started his independent research group and established ‘Stem cells, Leukemia, Aging and Metabolism (SLAM) Laboratory’ at the University Clinic of Hematology, Bern University Hospital, and Department for BioMedical Research (DBMR), University of Bern.
The Rao lab studies the biology of hematopoietic stem cells (HSCs) in normal and malignant hematopoiesis to identify leukemic stem cell specific dependencies and vulnerabilities for therapeutic targeting. HSCs are responsible for life-long production of all mature blood cell lineages, but also a cellular target for transforming events in hematologic malignancies. Consequently, leukemic (mutant) HSCs constitute ideal cellular targets for future therapeutic strategies. We are investigating the roles of metabolism, inflammation and age-associated changes in leukemic HSCs in driving leukemia initiation and progression. We use mouse models and primary patient samples of myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and multi-omics approaches. Our goal is to identify leukemic stem cell specific dependencies and vulnerabilities for targeted therapies. Ultimately, we aim to translate our findings obtained from the pre-clinical settings to clinics.
The major focus of our research lays in unraveling the early events and factors contributing to clonal expansion and myeloid leukemia initiation and progression.
1. Mechanisms of myeloid leukemia Initiation and Progression
Since the incidence and prevalence of myeloid leukemias increase with age, we are investigating the underlying age-associated factors (inflammation) and mechanisms that trigger clonal expansion and disease manifestation in myeloid leukemias. (Figure 1).
Acquisition of a somatic driver gene mutation (e.g. JAK2, TET2 or DNMT3a) in a single hematopoietic stem cell (HSC) is the initial event in clonal hematopoiesis leading to the emergence of a mutant HSC clone (marked red), which if not eliminated by the immunosurveillance mechanisms persists in small numbers. At this stage many of the affected individuals do not show signs of hematological malignancies, a phenomenon known as ‘clonal hematopoiesis of indeterminate potential’ (CHIP). Therefore, CHIP might represent a pre-leukemic state. This also suggests that additional factors determine whether hematopoietic stem cells carrying somatic gene mutations can expand and reach a critical clonal size that becomes self-sustaining and disease-initiating.
We are investigating the roles of metabolism and inflammation in driving clonal expansion, leukemia progression and therapy resistance.
2. Cancer metabolism and biomarkers of myeloid Leukemias
To unravel the metabolic basis of MPN pathogenesis, we are studying the metabolic liabilities of leukemic stem cells. We recently uncovered that metabolic rewiring in hematopoietic cells is fundamental to the progression of mutant JAK2 driven MPNs. We demonstrated the feasibility and benefits of targeting altered glucose metabolism in MPN cells in vivo (Figure 2). Ongoing studies are focusing on elucidating the roles and therapeutic viability of various other dysregulated metabolic pathways in leukemic stem cells for targeted therapies.
3. Hematopoietic stem cell heterogeneity and drug response and resistance in myeloid leukemias
We are investigating how hematopoietic stem cell (HSC) sub-populations ( e.g. heterogeneity and lineage biased stem cells) contribute to myeloid leukemia pathogenesis and how these populations are perturbed in response to therapies and contribute to the drug resistance. We recently uncovered that the frequency of myeloid/megakaryocyte biased CD41high HSC subset was significantly increased in mutant JAK2 expressing mice and in patients with MPN. We are studying the functional and therapeutic relevance of lineage biased CD41high HSCs in MPN pathogenesis (Figure 3).
List of collaborators
- Prof. Dr. med. Anne Angelillo-Scherrer (Bern University Hospital)
- PD. Dr. med. Alicia Rovó (Bern University Hospital)
- Prof. Dr. Nicolas Bonadies (Bern University Hospital)
- PD. Dr. Amiq Gazdhar (Bern University Hospital)
- Dr. Naomi A. Porret (Bern University Hospital)
- Prof. Dr. med. Stefan Dirnhofer (USB, Basel)
- Prof. Dr. med. Radek C. Skoda, University Hospital Basel and University of Basel
- Prof. Dr. Amy Wagers (Harvard University and Harvard Medical School, USA)
- Prof. Dr. Anthony R Green (Cambridge, UK)
- Prof. Dr. Vikas Gupta (UHN Toronto, Canada)
- Prof. Dr. med. Dominik Wolf (Medical University of Innsbruck, Austria)
- Prof. Dr. med. Steffen Koschmieder (RWTH University Clinic Aachen, Germany)
- Prof. Dr. Samir Softic / Prof. Dr. Andrew N. Lane, (University of Kentucky, USA)
- Prof. Dr. Young C Jang (Georgia Institute of Technology, Atlanta, USA)
- Prof. Dr. med. Nikolaus Kröger/ Dr. Ioanna Triviai (UKE, Hamburg, Germany)
- Prof. Dr. John Pimanda (UNSW Sydney, Australia)
- Prof. Dr. Ross L. Levine, Memorial Sloan Kettering Cancer Center, New York, USA
- Swiss National Science Foundation (SNF)
- Inselspital Bern
- Swiss Cancer League
- The Novartis Foundation for medical-biological Research
- Chanias I, Stojkov K, Stehle GT, Daskalakis M, Simeunovic H, Njue LM, Schnegg-Kaufmann AS, Porret NA, Allam R, Rao TN, Benz R, Ruefer A, Schmidt A, Adler M, Rovo A, Balabanov S, Stuessi G, Bacher U, Bonadies N, On Behalf Of The Swiss Mds Study Group. Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine. Cancers (Basel). 2021 Jun 30;13(13):3296. doi: 10.3390/cancers13133296. PMID: 34209457.
- Rao TN*, Hansen N, Jan S, Paz DL, Kalmer M, Hilfiker J, Endele M, Ahmed N, Rybarikova M, Geier F, Beisel C, Hao-Shen H, Dirnhofer S, Schroeder T, Brümmendorf TH, Wolf D, Koschmeider S, Skoda RC*. JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by lower long-term functionality. Blood. February 2021. PMID: 33667305. (*Corresponding authors).
Highlighted by Dunbar A and Levine RL, Interferon with MPN hematopoietic stem cells. Blood (2021).
- Ronny N, Ashcroft P, Zmajkovic J, Rai S, Rao TN, Drexler B, Meyer SC, Lundberg P, Passweg JR, Leković D, Cokic V, Bonhoeffer S and Skoda R. MPN patients with low mutant JAK2 allele burden show late expansion restricted to erythroid and megakaryocytic lineages. Blood, July 2020. PMID: 32698197.
- Øbro NF, Grinfeld J, Belmonte M, Irvine M, Shepherd, MS, Rao TN, Karow A, Riedel LM, Harris OB, Prick JCM, Desai N, Miller A, Baxter EJ, Nangalia J, Godfrey A, Harrison C, Li J, Skoda RC, Campbell PJ, Green AR, and Kent DG. Longitudinal cytokine profiling identifies GRO-α and EGF as a potential biomarkers of disease progression in essential thrombocythemia. HemaSphere. 2020. 21;4(3): e371. PMID: 32647796.
- Rao TN, Kumar S, Pulikkottil AJ, George F, Beckel F, Fehling HJ. Novel, non-gene-destructive knock-in reporter mice refute the concept of mono-allelic Gata3 expression function. Journal of Immunology, 2020. 204 (9): 2600-2611; PMID: 32213568.
- Rao TN. The relevance of chronic inflammation for genomic instability in cancers. Spectrum Onkologie. 2020. 02/2020, 20-24.
- Rao TN*, Hansen N, Hilfiker J, Rai S, Majewska J, Leković D, Gezer D, Andina N, Galli S, Cassel T, Geier F, Delezie J, Nienhold R, Hao-Shen H, Beisel C, Palma SD, Dimeloe S, Trebicka J, Wolf D, Gassmann M, Fan TWM, Lane AN, Handschin C, Dirnhofer S, Kröger N, Hess C, Radimerski T, Koschmieder S, Čokić VP, and Skoda RC*. Metabolic alterations in JAK2 mutant hematopoietic cells represent therapeutic vulnerabilities for myeloproliferative neoplasms. Blood. 2019. 134(21):1832-1846. PMID: 31511238.
Highlighted by Brierley CK and Psaila B. Sugar thieves and addicts: nutrient subversion in JAK2 MPNs. Blood (2019) 134 (21): 1778–1780.
- Rao TN*, Gupta MK, Softic S, Wang LD, Jang YC, Thomou T, Bezy O, Kulkarni RN, Kahn CR, and Wagers AJ*. Attenuation of PKCδ activity enhances metabolic activity and regenerative capacity of blood progenitors. The EMBO Journal, 2018. 37(24):e100409; PMID: 30446598.
- Stadhouders R, Li BWS, de Bruijn MJW, Gomez A, Rao TN, Fehling HJ, van IJcken WFJ, Lim AI, Di Santo JP, Graf T, Hendriks RW. Epigenome analysis links gene regulatory elements in group 2 innate lymphocytes to asthma susceptibility. Journal of Allergy Clinical Immunology. 2018. PMID: 29486229.
- Li BWS, Stadhouders R, de Bruijn MJW, Lukkes M, Beerens DMJM, Brem MD, KleinJan A, Bergen I, Vroman H, Kool M, van I Jcken WFJ, Rao TN, Fehling HJ, Hendriks RW. Group 2 innate lymphoid cells exhibit a dynamic phenotype in allergic airway inflammation. Frontiers in Immunology. 2017. PMID: 29250067.
- Softic S, Wang G, Fujisaka S, O’Neill BT, Thomou T, Li E, Farris H, Rao TN, Willoughby J, Fitzgerald K, Newgard CB, Herrero L, Cohen DE, Kahn CR. Dietary fructose but not glucose, impairs mitochondrial fatty acid oxidation and accelerates NAFLD development. Journal of Clinical Investigation. 2017.Nov 1;127(11):4059-4074. PMID: 28972537.
- Thomou T, Marcelo MA, Dreyfuss J, Konishi M, Greenspoon SK, Masaji S, Jonathan W, Rao TN, Gracia R, Gorden P and Kahn CR. Adipose-derived circulating microRNAs regulate gene expression in other tissues. Nature. 2017 Feb 23;542(7642):450-455. PMID: 28199304.
- Grisouard J, Li S, Kubovcakova L, Rao TN, Lundberg P, Hao-Shen H, Romanet V, Murakamim M, Radimerski T, Dirnhofer S, and Skoda RC. JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis. Blood. 2016 Jun 10. PMID: 27288519.
- Katagiri, S, Park K, Maeda Y, Rao TN, Khamaisi, M, Li Q, Mima A, Lancerotto L, Wagers AJ, Orgill DP, King GL. Augmenting insulin signaling in endothelial cells via IRS1 overexpression improves angioblasts differentiation and wound healing in diabetes and insulin resistance. Diabetes. 2016 May 23, PMID: 27217486.
- Kowalczyk MS, Tirosh I, Heckl D, Rao TN, Hass B, Schneider-Kramann R, Wagers AJ, Ebert BL, and Regev A. Single cell RNA-Seq of hematopoietic stem cells reveals a cell cycle-dependent interplay between aging and differentiation. Genome Research. 2015. 25(12):1860-72.
- Gupta MK, Teo AKK, Rao TN, Bhatt S, De Jesus DF, Kleinridders A, Windmueller R, Hu J, Wagers AJ, and Kulkarni RN. Excessive cellular proliferation negatively impacts reprogramming efficiency of human fibroblasts into iPS cells. Stem Cells Translational Medicine. 2015 Oct:4(10):1101-8. PMID: 26253715.
- Wang LD*, Rao TN*, Nguyen P, Sullivan J, Pearson D, Rowe RG, Doulatov S, Linsley CR, Hao Zhu, DeAngelo D, Daley GQ, and Wagers AJ. The role of Lin28 in myeloid and mast cell differentiation and mast cell malignancy. Leukemia 2015, Jun;29(6):1320-30. PMID: 25840412.
- Rao TN, Marks-Bluth J, Sullivan J, Gupta MK, Jang YC, Chandrakanthan V, Fitch S, Ottersbach K, Kulkarni RN, Piao X, Serwold T, Pimanda JE, and Wagers AJ. High-level Gpr56 expression is dispensable for the maintenance and function of hematopoietic stem and progenitor cells in mice. Stem Cell Research. 2015 May;14(3):307-22. PMID: 25655194.