1. Ph.D. programme
(a) Candidates should be M.Sc. (any branch of science)/M. Tech or equivalent qualification with minimum 60% marks (or equivalent grade point). Candidates awaiting final results may also apply, however, they have to produce their final mark sheet before any final decision is taken.
(b) Candidates should have qualified in CSIR/UGC-JRF or ICMR-JRF or DBT-JRF or DST-INSPIRE. They should have a valid fellowship for the full term. They should have qualified in any one of these examinations conducted not earlier than last one year.
The upper age limit of the candidate should be below 28 years on the date of application. Age relaxation will be given for five years in case of candidates belonging to SC/ST/women/PH and three years in case of OBC (as approved by Govt. of India) candidates.
If your qualification is matching with the above, email (firstname.lastname@example.org) or post your CV to me with all the other supporting documents. Please be advised that you have to come down to meet me before any final decision is taken.
2. Post-Doc programme
Ph.D. related to leukemia or solid cancer or cell biology.
If you are interested send an e-mail to me with your CV and one-page write-up about your thesis work. I can help you in writing a research grant for your fellowship. I need a commitment from you for at least 2 years in my lab. Please be advised that you have to come down for a discussion before any final decision is taken.
My lab is also looking for a bioinformatician who can handle TCGA, GEO, other big databases and have a working knowledge with Bioconductor.
Ph.D in Science (Microbiology): National Institute of Cholera and Enteric Diseases, Calcutta, under the supervision of Dr. G. Balakrish Nair.
|Loyola University Medical Center||Research Associate||Jan, 2000 to April, 2001|
|University of Illinois at Chicago||Research Associate||May, 2001 to June, 2002|
|University of Illinois at Chicago||Instructor||June, 2002 to June, 2003|
|University of Illinois at Chicago||Research Assistant Professor||June, 2003 to Jan, 2005|
|Institute of Life Sciences||Lecturer, converted to Scientist-B||Feb, 2005 to May, 2007|
|Institute of Life Sciences||Scientist-C||June, 2007 to May, 2011|
|Institute of Life Sciences||Scientist-D||June, 2011 to June, 2015|
|Institute of Life Sciences||Scientist-E||July, 2015 to till date|
ICMR International fellowship, Feb to July, 2011
Prof. Catherine M. Verfaillie
Stem Cell Institute, Katholieke Universiteit, Leuven, Belgium.
Project: Development of Myelodysplastic Syndrome (MDS) in mice.
|National/International||Name of body, society, Academy||Position||Year||Validity|
|National||Indian Association of Cancer Research (IACR) *||Life member||2012 to till date||Lifetime|
|Chronic disease biology (CDB) Task force, Dept. of Biotechnology, Govt. of India.||Member||2009 -2014||6 years|
|Bio-safety Committee, National Institute of Science, Education and Research, (NISER) Bhubaneswar, India.||DBT nominee||2009-2013||3 years|
|Society of Biological Chemists (SBC)||Life member||2013||Lifetime|
|International||American Association of Cancer Research (AACR)||Active member||2012 to till date||—-|
|European Haematology Association (EHA)||Member||2015 to till date||—–|
1. Chronic myeloid leukemia disease progression
Complete understanding of the role of specific genes (known or novel) in the progression of a disease can have a profound impact on the diagnosis, therapy, and ultimately the survival of the patients. There is a genuine need for the discovery of molecular mechanisms that delineates leukemic stem cells from normal stem cells and the research findings may lead to targeted molecular therapies that can block specific abnormalities found in leukemic patients.
BCR-ABL mediated repression of miR-223 results in the activation of MEF2C and PTBP2 in chronic myeloid leukemia
Agatheeswaran et al., 2012
We have reported here that miR-223 downregulation affects the transcription factor MEF2C and alternative splicing factor PTBP2. Our results suggest that changes in the miR-223/PTBP2 pathway can contribute to an abnormal splicing of several genes and shed light into the potential role exerted by miRNAs in a subset of CML. Not only did it highlight the ability of miRNAs to alter mRNA but also, more importantly, it added a new layer to the complexity of mechanisms regulating the phenotype of CML.
JAK inhibitors along with TKIs can eradicate CML lineage negative cells
Agatheeswaran et al., 2014
CML lin(-) cells from the bone marrow of naive CML cases were purified by using CML debulking kit. Approximately 80% of the lin(-) cells were found to be positive for CD34 marker. We observed that imatinib efficiently blocks the BCR-ABL kinase activity but failed to eliminate the CML lin(-) cells in an in vitro culture system when supplemented with cytokines. However, a combination of imatinib and JAK inhibitor 1 brought down the cell proliferation significantly. The combination of the imatinib and JAK inhibitor 1 also showed a significant decrease in BCR-ABL/BCR ratio with respect to imatinib alone. Our results suggests the fact that combination of TKI inhibitor along with a JAK inhibitor can efficiently eliminate CD34+ CML cells and in the process residual normal stem and progenitor cells can expand considerably.
MEF2C and CEBPA: possible co-regulators in Chronic Myeloid Leukemia disease progression
Agatheeswaran S and Chakraborty S, 2016
Chronic myelogenous leukemia (CML), a hematopoietic malignancy, characterized initially by a chronic phase (CP) progresses into blast crisis (BC) with the accumulation of secondary abnormalities. We have reported earlier that MEF2C, a target of miR-223, was significantly up regulated in CML and also showed a negative correlation with miR-223. In this study, gene expression arrays were used to identify the genes regulated by MEF2C during myelopoiesis. Statistical tools were used to understand the correlation between MEF2C and the targets in different phases of CML. Different CML cell lines and CML patient samples were treated with imatinib to study the effect of MEF2C on the target genes. We observed that MEF2C targets a set of myeloid genes including the myeloid transcription factor CEBPA. MEF2C and CEBPA expression patterns are negatively correlated in CML patient samples. We further show that the expression of MEF2C and CEBPA along with CSF3R is sufficient to molecularly classify different stages of CML. Imatinib, the drug of choice for CML, abrogates MEF2C expression and reverses CEBPA repression both in the cell line and the primary cells. We report the existence of a MEF2C and CEBPA correlation in CML disease progression.
Identification and functional characterization of the miRNA-gene regulatory network in chronic myeloid leukemia lineage negative cells
Agatheeswaran S, 2016
Chronic myeloid leukemia (CML) is maintained by leukemic stem cells (LSCs) which are resistant to the existing TKI therapy. Hence a better understanding of the CML LSCs is necessary to eradicate these cells and achieve complete cure. Using the miRNA-gene interaction networks from the CML lin(-) cells we identified a set of up/down-regulated miRNAs and corresponding target genes. Association studies (Pearson correlation) from the miRNA and gene expression data showed that miR-1469 and miR-1972 have significantly higher number of target genes, 75 and 50 respectively. We observed that miR-1972 induces G2-M cell cycle arrest and miR-1469 moderately arrested G1 cell cycle when overexpressed in KCL22 cells. We have earlier shown that a combination of imatinib and JAK inhibitor I can significantly bring down the proliferation of CML lineage negative cells. Here we observed that Imatinib and JAK inhibitor I combination restored the expression pattern of the down-regulated miRNAs in primary CML lin(-) cells. Thus effective manipulation of the deregulated miRNAs can restore the miRNA-mRNA networks that can efficiently inhibit CML stem and progenitor cells and alleviate the disease.
Dual transcripts of BCR–ABL and different polymorphisms in Chronic Myeloid Leukemia patients from Odisha, India
Nandagopalan et al., 2015
Chronic myeloid leukemia is characterized by the presence of a hallmark chromosomal translocation, the Philadelphia chromosome. It is the commonest form of adult leukemia in the Indian population. Although there is no dearth of reports regarding the different variants of BCR-ABL in the literature, we studied the co-expression of e13a2 and e14a2 transcripts and few polymorphisms in CML patients from Odisha, India. Molecular genetics approach was adapted to screen for polymorphisms, mutation and translocation in BCR, ABL kinase domain and BCR-ABL breakpoint region in 73 CML patients. All 8 patients with dual transcripts were found to harbor an exonic polymorphism (c.2700 T>C) and an intronic polymorphism (g.109366A>G) that were earlier reported to be associated with co-expression of both the transcripts. We also observed c.763G>A mutation in ABL kinase domain that confers reduced sensitivity to tyrosine kinase inhibitors and two polymorphisms, c.2387 A>G and c.2736A>G in the BCR gene. Although our data supports the previous findings that co-expression of BCR-ABL transcripts is due to the occurrence of exonic and intronic polymorphisms in the BCR gene it also shows that the intronic polymorphism can arise without the linked exonic polymorphism in the Indian population. The occurrence of ABL kinase domain mutation is less frequent in Indian population. We also report the presence of N796S polymorphism that was earlier reported to be associated with bipolar disorder; however we were not able to find any significant correlation between CML disease occurrence and the polymorphism, its frequency was similar in the control population.
2. Consequences of post translational modification of the proto-oncogene EVI1 in solid tumor/leukemia and stem cells
Post-translational protein modification plays an important role in multiple cellular processes including DNA repair, protein stability, nuclear translocation, protein-protein interactions, and in cellular proliferation, differentiation and apoptosis. Multiple post translational modifications on a protein constitute a complex regulatory program that transduces molecular information to and from signalling pathways. Whether the cellular mechanisms coordinating post-translational modifications support leukemogenesis remains to be determined.
Acetylation of the proto-oncogene EVI1 abrogates Bcl-xL promoter binding and induces apoptosis
Pradhan et al., 2011
In this study we provide evidence that EVI1 directly induces the expression of Bcl-xL through the first set of zinc finger and thereby inhibits apoptosis. ChIP analysis showed that EVI1 binds to the Bcl-xL promoter in HT-29 cells, a colon carcinoma cell line, which expresses EVI1. The observation is also supported by the fact that EVI1 siRNA treated HT 29 cells, shows a down regulation of Bcl-xL expression and that over expression of EVI1 results in the induction of the Bcl-xL reporter construct. A set of EVI1 positive chronic myeloid leukemia (CML) samples also showed higher Bcl-xL expression with respect to EVI1 negative samples. Interestingly, co-expression of EVI1 with wild type, but not with dominant-negative form of PCAF, abolishes the effect of EVI1 on Bcl-xL, indicating that acetylation of EVI1 abrogates its ability not only to bind Bcl-xL promoter but also alleviate Bcl-xL activity. Finally we have shown that EVI1 expression regulates apoptosis in HT-29 cells, which is abrogated when HT-29 cells are transfected with EVI1 siRNA or PCAF. The result for the first time shows a direct pathway by which EVI1 can protect cells from apoptosis and also demonstrates that the pathway can be reversed when EVI1 is acetylated.
EVI1 up-regulates the stress responsive gene SIRT1 which triggers deacetylation and degradation of EVI1
Pradhan et al., 2011
In this report, we show that SIRT1, a histone deacetylase is a direct target of EVI1. In vivo chromatin immunoprecipitation assay revealed that EVI1 binds to the promoter region of SIRT1 approximately 1 kb upstream of the transcription start site. The functionality of the site was deduced by luciferase assay which showed that EVI1 significantly increases the SIRT1 promoter activity. SIRT1 was also found to be up regulated in cell lines and in chronic myeloid leukemia patient samples where EVI1 was detected. Over expression of SIRT1 in cells shows that it interacts with EVI1 and this interaction lead to the deacetylation of the protein. Upon deacetylation the stability of EVI1 was found to be affected which was negatively regulated by nicotinamide (NAM). Our results thus identify an EVI1-SIRT1 axis in the regulation of EVI1 activity suggesting a possible role of SIRT1 in EVI1 positive neoplasms.
EVI1 targets ∆Np63 and upregulates the cyclin dependent kinase inhibitor p21 independent of p53 to delay cell cycle progression and cell proliferation in colon cancer cells
Nayak et al., 2013
Our data for the first time shows that ecotropic viral integration site I binds to ∆Np63 promoter element directly and down regulates its expression. Down regulation of ∆Np63 induces the expression of p21 in HT-29cells and also in colon carcinoma cells that do not express p53 including patient samples expressing low level of p53, that eventually delay cell cycle progression at G0/G1 phase. Concomitant silencing of ecotropic viral integration site I from the cells or introduction of ∆Np63 to the cells significantly rescued this phenotype, indicating the growth defect induced by ∆Np63 deficiency to be, at least in part, attributable to ecotropic viral integration site I function. The mutual regulation between ecotropic viral integration site I and ∆Np63 may constitute a novel axis which might affect the downstream pathways in cells that do not express functional p53.
SUMO1 negatively regulates the transcriptional activity of EVI1 and significantly increases its co-localization with EVI1 after treatment with arsenic trioxide
Singh et al., 2013
Aberrant expression of the proto-oncogene EVI1 (ecotropic virus integration site1) has been implicated not only in myeloid or lymphoid malignancies but also in colon, ovarian and breast cancers. Despite its importance in oncogenesis, the regulatory factors and mechanisms that potentiate the function of EVI1 and its consequences are partially known. Here we demonstrated that EVI1 is post-translationally modified by SUMO1 at lysine residues 533, 698 and 874. Although both EVI1 and SUMO1 were found to co-localize in nuclear speckles, the sumoylation mutant of EVI1 failed to co-localize with SUMO1. Sumoylation abrogated the DNA binding efficiency of EVI1 and also affected EVI1 mediated transactivation. The SUMO ligase PIASy was found to play a bi-directional role on EVI1, PIASy enhanced EVI1 sumoylation and augmented sumoylated EVI1 mediated repression. PIASy was also found to interact with EVI1 and impaired EVI1 transcriptional activity independent of its ligase activity. Arsenic trioxide (ATO) known to act as an anti leukemic agent for acute promyelocytic leukemia (APL) not only enhanced EVI1 sumoylation but also enhanced the co-localization of EVI1 and SUMO1 in nuclear bodies distinct from PML nuclear bodies. ATO treatment also affected the Bcl-xL protein expression in EVI1 positive cell line. Thus, the results showed that arsenic treatment enhanced EVI1 sumoylation, deregulated Bcl-xL, which eventually may induce apoptosis in EVI1 positive cancer cells. The study for the first time explores and reports sumoylation of EVI1, which plays an essential role in regulating its function.
Physical and functional interaction of the proto-oncogene EVI1 and tumor suppressor gene HIC1 deregulates Bcl-xL mediated block in apoptosis
Pradhan et al., 2014
Several studies have established ecotropic viral integration site 1 as both a transcription factor and an interacting partner that presumably regulates gene expression. Using coimmunoprecipitation and fluorescence resonance energy transfer analysis, we found that the N-terminal domain of hypermethylated in cancer 1 interacts with the proximal set of zinc fingers of ecotropic viral integration site 1.This interaction not only abolishes the DNA binding activity of ecotropic viral integration site 1 but also disrupts the transcriptional activity of an anti-apoptotic gene promoter selectively targeted by ecotropic viral integration site 1. By using flow cytometry and western blotting, here we show that hypermethylated in cancer 1 can deregulate ecotropic viral integration site 1 mediated blockage of apoptosis. We hypothesize that therapeutic upregulation of hypermethylated in cancer 1 may provide an important means of targeting ecotropic viral integration site 1 positive cancers.
List of publications
A. During Ph.D
Anjan Pradhan: Biochemical and biological role of acetylation on the proto-oncogene EVI1
Sneha Singh: EVI1 sumoylation: site identification and functional characterization
Kasturibala Nayak : PKC mediated EVI1 phosphorylation: Biochemical and biological significance in promoting EVI1 mediated gene regulation.
S. Agatheeeswaran: Identification of miRNA – mRNA network present in chronic myeloid leukemia CD34+ stem cells
|Grant agency||Title of the project and Reference number||Duration, (from mm/yy to mm/yy)|
|DST, Govt. of India||Consequences of post-translational modification on the proto-oncogene EVI1||3 years, (Nov, 2006- Oct, 2009)|
|DBT, Govt. of India||Molecular monitoring of secondary mutations potentially involved in disease transformation of CML to CML-Blast Crisis.||3 years, (Nov, 2006- Oct, 2009)|
|DBT, Govt. of India||Deciphering SUMO-induced EVI1 signaling in promoting leukemogenesis||3 years, (July, 2011- June, 2014)|
|DST, Govt. of India||Identification of microRNA/mRNA regulatory network in haematopoietic stem cells isolated from patients with chronic myeloid leukemia||3 years, (Aug, 2012-July, 2015)|
|DBT, Govt. of India||Global profiling and significance of alternative splicing events regulated by polypyrimidine tract binding protein 2 (PTBP2) in the advanced stages of chronic myeloid leukemia||5 years, (2015-2020)
Recommended under Unit of Excellence (UOE) of DBT
|DST, Govt. of India||Comparative analysis of acetylation and acetylation deficient mutant form of Ecotropic Viral Integration site I in haematopoietic cells||3 years, (2015-2018)|
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