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Chozha V. Rathinam, Dr. rer. nat.

Academic Title:

Associate Professor

Primary Appointment:

Medicine

Additional Title:

Head, Laboratory of Stem Cell & Cancer Biology, The Institute of Human Virology

Location:

725 West Lombard Street, Baltimore, MD 21201

Phone (Primary):

410-706-6158

Phone (Secondary):

410-706-6168

Education and Training

I finished Master of Science (M.Sc.) in Life Sciences, a highly prestigious research oriented Integrated Masters Program in the country, at Bharathidasan University, India with distinction grades.

After having served as a Lecturer of Biotechnology at Bharathidasan University for a short time, I moved to Germany to pursue my doctoral (Dr. Rer. Nat.) studies at the Hannover Medical School, under the  supervision of Dr. Christoph Klein. My doctoral work unraveled  the key role of the transcription factor-Gfi1 in the differentiation of dendritic cells from Hematopoietic Stem Cells (HSCs).

My postdoctoral studies, in the laboratory of Dr. Richard Flavell, Yale University School of Medicine, New Haven, CT, highlighted the previously unappreciated, but physiologically significantly, roles of post-translational modifications  (Ubiquitylation) of proteins in the biology of HSCs  and Leukemic Stem Cells. Of note, this work was recognized as the “novel avenue of stem cell biology” by the experts in the field. In addition, I generated a novel line of humanized mouse models that shows superior engraft of Human HSCs and efficient development of human immune system under xenogenic settings.

In 2010, I served as a group leader at the NIH center for excellence in Stem Cell Biology, Providence, RI.  

In 2011, I became an Assistant Professor at the Department of Genetics & Development, Columbia University Medical Center, New York, NY. My lab at Columbia University focused on the role of inflammatory signals in the control of normal and leukemic stem cells.

In October- 2016, I joined the Institute of Human Virology, University of Maryland School of Medicine and my lab currently focuses on intrinsic and extrinsic molecular circuits that cause stem cell based pathophysiologies including Cancer, inflammatory disorders,  Immunodeficiencies and aging. 

Research/Clinical Keywords

Hematopoietic Stem Cells; Leukemic Stem Cells; Mesenchymal Stem Cells and Hematopoiesis

Highlighted Publications

 

1. Nakagawa M and Rathinam CV. Constitutive activation of the canonical NF-κB pathway leads to progressive Bone Marrow Failure and induction of Erythroid Transcriptional Program in Hematopoietic Stem Cells. Cell Reports 25, 2094-2109 (2018).

2. Nakagawa MM, Chen H and Rathinam CV. Constitutive activation of NF-kB pathway in hematopoietic stem cells causes loss of quiescence and deregulated transcription factor networks. Frontiers in Cell and Developmental Biology 6, 143 (2018).

3. Nakagawa M, Davis H and  Rathinam CV. A20 deficiency in Multipotent Progenitors perturbs quiescence of Hematopoietic Stem Cells. Stem Cell Research 33:199-205 (2018).

4. Lu K, Nakagawa MM, Thummar K and Rathinam CV. The Slicer Endonuclease Argonaute 2 is a Negative Regulator of Hematopoietic Stem Cell Quiescence. Stem Cells 34,1343-53 (2016)

5. Nakagawa MM, Thummar K, Mandelbaum J, Pasqualucci L and Rathinam CV. Lack of the Ubiquitin-Editing Enzyme A20 results in loss of Hematopoietic Stem Cell Quiescence. The Journal of Experimental Medicine 212, 203-16 (2015)

6. Rathinam CV. The 'Inflammatory' control of hematopoietic stem cells. Oncotarget 6,19938-9 (2015)

7. Rathinam CV, Majetic L and Flavell R. The HECT domain E3 ligase Itch negatively controls haematopoietic stem cell maintenance and functions. Nature Immunology 12, 399-407 (2011)

8. Rathinam CV, Thien C, Flavell Rand Langdon W. Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. Cancer Cell 18, 341-52 (2010)

9. Rathinam CV, Thien C, Langdon W, Gu H, Flavell R. The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells. Genes &  Development 22, 992-997 (2008).

10. Rathinam CV, Geffers R, Yücel R, Buer J, Welte K, Möröy T, Klein C. The transcriptional repressor Gfi1 controls STAT3-dependent dendritic cell development and –function. Immunity 22, 717-728 (2005).

Additional Publication Citations

1. Kode A, Mosialou I, Manavalan SJ, Rathinam CV, Friedman RA, Teruya-Feldstein J, Bhagat G, Berman E, Kousteni S. FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 30,1-13 (2016).

2. De A, Dainichi T, Rathinam CV and Ghosh S.The deubiquitinase activity of A20 is dispensable for NF-κB signaling. EMBO Reports15, 775-83 (2014).

3. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, Khiabanian H, Lee A, Murty VV, Friedman R, Brum A, Park D, Galili N, Mukherjee S, Teruya-Feldstein J, Raza A, Rabadan R, Berman E and Kousteni S. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506, 240-4 (2014).

4. Baldzizhar R, Fedorchuk C, Jha M, Rathinam CV, Henegariu O and Czyzyk J. Anti-serpin antibody mediated regulation of proteases in autoimmune diabetes. The Journal  of Biological Chemistry 288, 1612-9 (2013).

5. Kriegel MA, Rathinam CV and Flavell RA.Pancreatic Islet expression of Chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11C+CD11B+ Dendritic Cells. Proc Natl Acad Sci USA 109, 3457-62 (2012).

6. Ahmed N, Zeng M, Sinha I, Polin L, Wei WZ, Rathinam CV, Flavell R, Massoumi R and Venuprasad K. The E3 Ligase Itch and Deubiquitinase Cyld act together to regulate Tak1 and Inflammation. Nature Immunology, 12, 1176-83 (2011).

7. Rathinam CV, PoueymirouWT, RojasJ, MurphyAJ, ValenzuelaDM, YancopoulosGD, Rongvaux A, EynonEE, Manz  MG and FlavellRA. Efficient differentiation and functions of human macrophages in the humanized M-CSF mice. Blood 118, 3119-28 (2011).

8. Strowig T, Rongvaux A, Rathinam CV, Eynon EE, Manz MG and Flavell RA. Transgenic expression of human SIRPa improves the engraftment of human cells in Rag2-/- common gC-/- mice. Proc Natl Acad Sci USA 108, 13218-23 (2011).

9. Kamanaka M, Zenewicz LA, Huber S, Gagliani N, Rathinam CVO’ Connor W, Wan YY, Nakae S, Iwakura Y, Hao L and Flavell R. CD45RBlo CD4 T cells are controlled directly by IL-10 and cause IL-22 dependent colitis. The Journal of Experimental Medicine 208,1027-40 (2011).

10. Rongvaux A, Willinger T, Takizawa H, Rathinam CV, Wojtek A, Murphy AJ, Valenzuela DM, Yancopoulos GD, Eynon EE, Stevens S, Manz MG and Flavell RA. Human thrombopoietin Knock-in mice efficiently support human hematopoietic stem and progenitor cells. Proc Natl Acad Sci USA 108, 2378-83 (2011).

11.Rathinam CV and Flavell R. c-Cbl deficiency leads to diminished lymphocyte development and functions. Proc Natl Acad Sci USA107, 8316-21 (2010).

12.RathinamCV*, KriegelM* and FlavellR. E3 Ubiquitin Ligase GRAIL Controls Primary T Cell Activation and Oral Tolerance. Proc Natl Acad Sci USA 106, 16770-5 (2009). *Equal contribution & Indicated First

13. Legrand N, Ploss A, Balling R, Becker PD, Borsotti C, Brezillon N, Debarry J, de Jong Y, Deng H, Di Santo JP, Eisenbarth S, Eynon E, Flavell RA, Guzman CA, Huntington ND, Kremsdorf D, Manns MP, Manz MG, Mention JJ, Ott M, Rathinam C, Rice CM, Rongvaux A, Stevens S, Spits H, Strick-Marchand H, Takizawa H, van Lent AU, Wang C, Weijer K, Willinger T, Ziegler P. Humanized mice for modeling human infectious disease: challenges, progress, and outlook Cell Host Microbe 6, 5-9  (2009)

14.Rathinam CV*, Schwermann J*, Schubert M*, Schumacher S, Noyan F, Koseki H,  Kotlyarov A, Klein C, Gaestel M. MAPKAP Kinase MK2 maintains self-renewal capacity of hematopoietic stem cells. The EMBO Journal 28, 1392-406 (2009). *Equal contribution & Indicated First

15. Templin C, Kotlarz D, Rathinam CV, Rudolph C, Schätzlein S, Ramireddy K,    Rudolph KL, Schlegelberger B, Klein C, Drexler H.Establishment of immortalized multipotent hematopoietic progenitor cell lines by retroviral-mediated gene transfer of beta-catenin. Experimental Hematology 36, 204-15 (2008).

16.Rathinam CV and Flavell R. The hematopoiesis paradigm: clarity or ambiguity ? Blood 112, 3534-5 (2008).

17. Ju Z, Jiang H, Jaworski M, Rathinam CV, Gompf A, Klein C, Trumpp A, and Rudolph KL. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nature Medicine13, 742-747 (2007).

18. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, Rathinam CV, Boztug K, Schwinzer B, Rezaei N, Bohn G, Melin M, Carlsson G, Fadeel B, Dahl N, Palmblad J, Henter JI, Zeidler C, Grimbacher B, Welte K. Hax1 deficeincy causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nature Genetics 39, 86-92 (2007).

19. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schaffer AA, Rathinam CV, Taub N, Teis D, Zeidler C, Dewey RA, Geffers R, Buer J, Huber LA, Welte K, Grimbacher B, Klein C. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nature Medicine 13, 38-45 (2007).

20. Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam CV, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 108, 362-9 (2006).

21.Rathinam CV, Sauer M, Ghosh A, Rudolph C, Hegazy A, Schlegelberger B, Welte K, Klein C. Generation and characterisation of a novel hematopoietic progenitor cell line with DC differentiation potential. Leukemia 20, 870-6 (2006).

22. Saravanamuthu SS, von Gotz F, Salunkhe P,  Rathinam CV, Geffers R, Buer J,Tummler B, Steinmetz I.Evidence for polyadenylated mRNA in Pseudomonas aeruginosa. Journal of Bacteriology 186, 7015-8 (2004).

23. Krishnamurthy KVK , Krishnaraj R, Rathinam CV, Christopher S. The Programme Of Cell Death In Plants and Animals -A Comparison. Current Science 79 (2000).

Research Interests

The major lines of our current investigation include:

 

Decode the genetic basis of self-renewal of Hematopoietic Stem Cells: Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate into all lineages of the hematopoietic compartment. A constellation of intrinsic and extrinsic cellular mechanisms regulate self-renewal versus differentiation of HSCs. In the past few decades, significant progress has been made towards the understanding of cellular and molecular identities of HSCs. Nonetheless, the molecular machinery that controls the “stemness” of HSCs remains largely unknown.  In an attempt to unravel the significance of post-translational modifications in the self-renewal, we identified the importance of 2 major families of E3 ubiquitin ligases; 1. RING finger family- c-Cbl and2. HECT family–Itch in the self-renewal of HSCs. These studies have unequivocally proven the importance of ubiquitylation events and E3 ligases in the control of HSC development and functions. Of note, our approach of ‘decoding self-renewal of stem cells through ubiquitylation’ has been considered as a novel avenue of stem cell biology by the experts in the field (Yokomizo and Dzierzak, Genes and development, 2008). Even though our earlier studies have provided clues on the significance and physiological relevance of post-translation modifications in HSCs, still much work needs to be done in this area in order to understand the mechanisms and pathways through which self-renewal of HSCs is regulated. To this end, we are intensively investigating the importance and specificity of E3 ubiquitin ligases in the self-renewal process.

Decipher aberrant molecular events that give rise to Leukemic Stem Cells: One of the major challenges in cancer biology is to define aberrant molecular pathways that cause transformation of normal stem cells to cancer stem cells. Pioneering studies over a decade have highlighted the phenotypic and functional similarities between normal stem cells and cancer stem cells.  Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-renewing cancer cells and tumor formation. We recently documented that a deficiency in c-Cbl mediated ubiquitylation events results in the transformation of normal HSCs into Leukemic Stem Cells (LSCs). Strikingly, when we blocked signal transduction pathways mediated through the cytokine-Flt3L in HSCs, the onset of leukemia in c-Cbl mutant animals is prevented. In line with our observations, recent studies from several groups have reported that human cancers including MPD, AML and JMML are associated with frequent mutations in c-CBL. Overall,these observations highlight the importance of ubiquitylation events and underline the key functions of E3 ubiquitin ligases in the prevention of hematologic cancer.  Currently, we are actively engaged in the identification of signal transduction pathways that contribute to the transformation of normal HSCs into LSCs.  In addition, we focus on the importance of post-translational modifications of signal transducers in the phenomenon of Leukemic transformation.  

 Unravel the molecular identities of Mesenchymal Stem Cells: Mesenchymal Stem Cells (MSCs) are multipotent stem cells that can differentiate into many lineages, including Osteoblasts, Chondrocytes, Myocytes and Adipocytes. MSCs also play a very important role in immune modulation through secretion of a variety of cytokines, growth factors and chemokines. Recently, MSCs and its progenies are shown to form and control the hematopoietic “niche” of the bone marrow. These properties make these specialized cells potentially ideal candidates for tissue engineering and cell based therapies.  While MSCs hold a great promise as therapeutic agents in regenerative medicine, the cellular and molecular identities of MSCs are not well elucidated. In fact, only in the past few years the exact immunophenotype of murine MSCs has been described. In an effort to contribute to a better understanding of MSC biology, we are interested in uncovering both extrinsic and intrinsic control of MSC self-renewal and functions. 

 

We currently looking for highly motivated students and postdoctoral fellows. 

Awards and Affiliations

2015  BD Immunology Award

2014  New Innovator Award, Leukemia Research Foundation, USA

2007  Best Ph.D thesis work award, University of Tubingen, Germany

2005  ASH Travel Award, American Society  of Hematology, USA

2000  Best Research Presentation Award, SASTRA University, India

Grants and Contracts

Current:

 

2017-2022       1R01HL132194-01 (Role: Principal Investigator)

                          NF-kB signaling in the control of Hematopoiesis

                          National Institutes of Health/National Heart Lung Blood Institute  (NHLBI)

 

2015-               Role: Principal Investigator

                         "Itchy" basophils of the Immune System

                         BD Biosciences Immunology Grant

 

Completed:

 

2014-2015      Role: Principal Investigator

                        Role of A20 in the restriction of myeloid Leukemia

                        Leukemia Research Foundation

 

2010-2011     Role: Lead Investigator

                       Genetic & Molecular Control of E3 Ubiquitin Ligases in Stem Differentiation

                       National Institues of Health (NCRR),  5P20RR018757-09