Dr. Poonkuzhali Balasubramanian – Department of Haematology

Dr. Poonkuzhali Balasubramanian M.Sc., Ph.D

Professor

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Career Interests Research Publications Bio data

Career Interests

Pharmacogenetics of anticancer agents
Molecular genetics of leukemia
Anticancer drug resistance
Conditioning regimen in hematopoietic stem cell transplantation

Research

Research interests

Anticancer Drug Resistance- Mechanisms and Modulation

We are trying to understand the mechanisms of anticancer drug resistance in myeloid leukemias. Acute myeloid leukemia (AML) is a biologically, clinically and genetically heterogeneous disease characterized by increased proliferation and defective maturation affecting the cells of the myeloid lineage. The backbone of AML treatment for the last 30 years has been the combination of daunorubicin and cytosine arabinoside (Ara-C). The BCR/ABL tyrosine kinase Imatinib mesylate (IM) is the mainstay of treatment for CML but does not eliminate primitive leukemia stem and progenitor cells. Residual leukemia cells are a potential source of relapse, and there is considerable interest in identifying additional therapeutic targets to selectively induce apoptosis in leukemic stem and progenitor cells. We attempt to extend the understanding of novel biology of leukemias with an effort to understand potential novel targets in AML, as well as to better understand mechanisms of resistance and intolerance to therapy in Chronic myeloid leukemia (CML). Our research is proposed to identify novel NHR genes as drug targets to overcome drug resistance in myeloid leukemias.

Targeted therapy with BCR-ABL tyrosine kinase inhibitors has tremendously improved the outcome of chronic myeloid leukemia (CML). However, about 15-20% patients treated with imatinib develop resistance or intolerance to the drug resulting in disease progression. Hence adequate molecular tools are required to diagnose, prognosticate and monitor minimal residual disease to make appropriate decisions on continuing therapy or changing. This decision process is compounded by the high cost of these second generation drugs in a predominantly self-paying system as exists in our country. In this project we plan to work towards an integrated model with a combination of the existing and novel parameters to more accurately prognosticate response to therapy in these patients. We believe that such a model working towards a cost effective therapy in patients with CML is critical for patients in our country where the cost of second generation TKI is prohibitive for most. Using a multidisciplinary approach, we anticipate that this study will have sufficient strength to arrive at genetic/prognostic signatures to identify poor responders and personalize therapy which could result in better treatment outcome. By exploring the mechanisms of disease progression, intolerance and resistance to imatinib using various genomic and cellular approaches, we anticipate that this study will eventually aid in personalizing tyrosine kinase inhibitor therapy in this disease.

Personalizing conditioning regimen in hematopoietic stem cell transplantation

Another major area of research in our laboratory is personalizing the conditioning regimen used in preparing patients for haematopoietic stem cell transplantation. Please see the link below for more details.
( https://www.indiaalliance.org/fellow/poonkuzhali-balasubramanian)

Team

	Dr. Bharathi Rajamani Post Doctoral fellow
	Mr. Stallon Illangeswaran R.S. Senior Research Fellow Ph.D student (Thiruvalluvar university, Vellore) My work focuses on targetting the nuclear hormone receptor family to overcome drug resistance and leukemic stem cells in acute myeloid leukaemia
	Ms. Saswati Das Senior Research Fellow (UGC/CSIR) Ph.D student (Thiruvalluvar university, Vellore) My work basically focuses on: The modulation of chemoresistance in Acute myeloid leukemia targeting epigenetic factors
	Ms. Esther Sathyabama Senior Research Fellow (DST-INSPIRE) PhD Student (SCTIMST, Trivandrum) My work focuses on modelling patient derived induced pluripotent stem cells (iPSCs) to understand drug resistant mechanisms in chronic myeloid leukaemia (CML)
	Mr. Aswin Anand Pai Senior Research Fellow (DBT) PhD Student (SCTIMST, Trivandrum) My research involves personalizing conditioning regimen in Haematopoietic Stem Cell Transplantation. I specifically focus on exploring Pharmacokinetics (PK), Pharmacogenomics (PG) and Pharmacodynamics (PD) of Treosulfan/Fludarabine which could help in optimizing stem cell transplantation for patients with beta-Thalassemia.
	Mr. Daniel Zechariah Paul Senior Research Fellow (ICMR-SRF) PhD. Student (MAHE, Manipal) My work primarily focuses on understanding the NRF2 mediated acquired drug resistance in AML to chemotherapeutic agents such as cytarabine, anthracycline and arsenic trioxide.
	Ms. Rakhi T V Junior Research Fellow (CSIR/UGC) PhD Student (RCB, Faridabad) Understanding RXRA-mediated improved tyrosine kinase inhibitor sensitivity in myeloid leukemias
	Ms. Nayanthara K B Junior Research Fellow (CSIR/UGC) PhD Student (RCB, Faridabad) Understanding the variations in the Pharmacokinetics, Pharmacogenomics and Pharmacodynamics of immunosuppressants on Haematopoietic cell transplantation (HCT) outcomes in patients undergoing Haploidentical HCT with post-transplant Cyclophosphamide as GVHD prophylaxis
	Ms. Rachel Mariam Renji Junior Research Fellow PhD Student (RCB, Faridabad) Evaluating factors predicting early post- transplant outcomes in patients receiving Treosulfan/Fludarabine conditioning regimen
	Mr. Arnab Maity Junior Research Fellow (UGC/CSIR) PhD Student (RCB, Faridabad) Strategies to deliver wildtype TP53 to myeloid leukemia cells to circumvent drug resistance

Research Technicians

Nivetha.E

Research Support: Ongoing Research Projects as Principal Investigator-5

Title of Project	Funding Agency	Amount (Lakhs)	Date of sanction and Duration
Can anti-helminthics improve chemo-sensitivity in acute myeloid leukemia by mediating nuclear hormone receptor expression?	DST-CRG	67.27	February 2022-2025
Strategies to optimize the treosulfan/thiotepa/fludarabine regimen and post- transplantation cyclophosphamide regimen	DBT India Alliance	449.9	January 2023-2028
Targeting myeloid leukemia stem cells derived from induced pluripotent stem cells (iPSCs) using high-throughput screening of FDA-approved drugs to overcome drug resistance. Co-PI	DST-CRG	74.48	September 2023-2026

Completed Research Projects (major projects of last 3 years)

Title of Project	Funding Agency	Amount (Lakhs)	Date of sanction and Duration
Modulation of chemoresistance in acute myeloid leukemia by Nrf2 and its downstream targets	Department of Science and Technology	45.4	September 2018, 36 months
ICMR Advanced Centre for Clinical Pharmacology in Hematological Diseases Aiming at Personalized Medicine	ICMR	93.7	March 2018, 36 months
Personalizing conditioning regimen in hematopoietic stem cell transplantation	Wellcome DBT	445	Oct2015, 60 months
Identification of novel nuclear receptors (NHR) drug targets in myeloid leukemia	DBT	75.75	Nov2015, 60 months
Exploring the mechanisms of disease progression, tyrosine kinase inhibitor resistance and intolerance in Chronic Myeloid Leukemia	DBT	83.65	Nov2015, 60 months

Alumni

Research Fellows:

Dr. Ajay Abraham, Postdoctoral fellow, University of Alabama at Birmingham
Ms. Sukanya Ganesan
Ms. Lakshmi Kailasam
Ms. Preetha Markose, Research Professional, University of the Sciences in Philadelphia
Ms. Ayisha Sithika M
Ms. Pravani Sukumaran
Dr. Savitha Varatharajan
Dr. Sreeja Karathedath – Scientist-I Research and development, Thermo Fischer scientific
Dr. Ezhilpavai Mohanan
Dr. Balaji, Assistant Professor, VIT
Ms. Infencia Xavier Raj
Mr. Ajith Mohan

Short term project students

Mr. Keshav Bharadwaj, Shoolini University, Himachal Pradesh (2012)
Mr. Sudershan Dhiman, Shoolini University, Himachal Pradesh (2013)
Ms. Dantuluri Swati, VIT Vellore (2013)
Ms. Vrindha Ghambir, VIT Vellore (2013)
Mr. Stavan Arulanand, Amity University, New Delhi (2014)
Ms. Shravanthi, PSG Coimbatore (2014)
Ms. Nisha Jain, VIT Vellore (2016)
Ms. Kezia Kanimozhi, VIT Vellore (2018)
Mr. Kumarappa T., Barathidasan University (2021)
Ms. Kaviyarasi R., Barathidasan University (2021)
Ms. Chelsea Josephine Charles, VIT Vellore (2023)
Mr. Raja T., IIT Guwahati (2023)

Publications

The detail list of my publications can be accessed at:

https://pubmed.ncbi.nlm.nih.gov/?term=Poonkuzhali+Balasubramanian&filter=simsearch3.fft&sort=date&size=50

My recent publications are:

Balakrishnan B, Illangeswaran RSS, Rajamani BM, Arunachalam AK, Pai AA, Mohanan E, Srivastava A, Mathews V, Balasubramanian P. Metformin pretreatment ameliorates busulfan-induced liver endothelial toxicity during haematopoietic stem cell transplantation. PLoS One. 2023 Oct 26;18(10):e0293311. doi: 10.1371/journal.pone.0293311. PMID: 37883349; PMCID: PMC10602364.
Pai AA, Mohanan E, Panetta JC, Kulkarni UP, Illangeswaran RSS, Balakrishnan B, Jayaraman A, Edison ES, Lakshmi KM, Devasia AJ, Fouzia NA, Korula A, Abraham A, George B, Srivastava A, Mathews V, Standing JF, Balasubramanian P. Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation. Clin Pharmacol Ther. 2024 Jan;115(1):116-125. doi: 10.1002/cpt.3078. Epub 2023 Nov 7. PMID: 37846495.
Kulkarni U, Arunachalam AK, Palani HK, Nair RR, Balasundaram N, Venkatraman A, Korula A, Selvarajan S, Lionel S, Balasubramanian P, Maddali M, Abraham A, George B, Mathews V. Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia. Cell Transplant. 2023 Jan-Dec;32:9636897231198178. doi: 10.1177/09636897231198178. PMID: 37706453; PMCID: PMC10503284.
Arunachalam AK, Selvarajan S, Mani T, Janet NB, Maddali M, Lionel SA, Kulkarni U, Korula A, Aboobacker FN, Abraham A, George B, Balasubramanian P, Mathews V. Clinical significance of end of induction measurable residual disease monitoring in B-cell acute lymphoblastic leukemia: A single center experience. Cytometry B Clin Cytom. 2023 Nov;104(6):440-452. doi: 10.1002/cyto.b.22139. Epub 2023 Aug 9. PMID: 37555390.
Kulkarni UP, Selvarajan S, Fouzia NA, Lionel S, Nair SC, Balasubramanian P, Mani T, Abraham A, George B, Mathews V. Intracranial bleeding in acute promyelocytic leukemia treated with arsenic trioxide based regimens is associated with induction mortality but not with relapse. Blood Cancer J. 2023 Jun 22;13(1):94. doi: 10.1038/s41408-023-00873-z. PMID: 37349334; PMCID: PMC10287743.
Rajamani BM, Illangeswaran RSS, Benjamin ESB, Balakrishnan B, Jebanesan DZP, Das S, Pai AA, Vidhyadharan RT, Mohan A, Karathedath S, Abraham A, Mathews V, Velayudhan SR, Balasubramanian P. Modulating retinoid-X-receptor alpha (RXRA) expression sensitizes chronic myeloid leukemia cells to imatinib in vitro and reduces disease burden in vivo. Front Pharmacol. 2023 May 31;14:1187066. doi: 10.3389/fphar.2023.1187066. PMID: 37324449; PMCID: PMC10264673.
Illangeswaran RSS, Jebanesan DZP, Sivakumar KK, Vidhyadharan RT, Rajamani BM, Janet NB, David E, Velayudhan SR, Mathews V, Balasubramanian P. Corrigendum to “Chemotherapeutic drugs elicit stemness and metabolic alteration to mediate acquired drug-resistant phenotype in acute myeloid leukemia cell lines” [Leukemia Res. 128, 107054]. Leuk Res. 2023 Jul;130:107329. doi: 10.1016/j.leukres.2023.107329. Epub 2023 May 29. Erratum for: Leuk Res. 2023 May;128:107054. PMID: 37258357.
Venkatesan V, Christopher AC, Rhiel M, Azhagiri MKK, Babu P, Walavalkar K, Saravanan B, Andrieux G, Rangaraj S, Srinivasan S, Karuppusamy KV, Jacob A, Bagchi A, Pai AA, Nakamura Y, Kurita R, Balasubramanian P, Pai R, Marepally SK, Mohankumar KM, Velayudhan SR, Boerries M, Notani D, Cathomen T, Srivastava A, Thangavel S. Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies. Mol Ther Nucleic Acids. 2023 Apr 26;32:671-688. doi: 10.1016/j.omtn.2023.04.024. PMID: 37215154; PMCID: PMC10197010.
Illangeswaran RSS, Jebanesan DZP, Sivakumar KK, Vidhyadharan RT, Rajamani BM, Janet NB, David E, Velayudhan SR, Mathews V, Balasubramanian P. Chemotherapeutic drugs elicit stemness and metabolic alteration to mediate acquired drug-resistant phenotype in acute myeloid leukemia cell lines. Leuk Res. 2023 May;128:107054. doi: 10.1016/j.leukres.2023.107054. Epub 2023 Mar 3. Erratum in: Leuk Res. 2023 Jul;130:107329. PMID: 36906941.
Balakrishnan B, Kulkarni UP, Pai AA, Illangeswaran RSS, Mohanan E, Mathews V, George B, Balasubramanian P. Biomarkers for early complications post hematopoietic cell transplantation: Insights and challenges. Front Immunol. 2023 Feb 2;14:1100306. doi: 10.3389/fimmu.2023.1100306. PMID: 36817455; PMCID: PMC9932777.
George A, Ravi NS, Prasad K, Panigrahi L, Koikkara S, Rajendiran V, Devaraju N, Paul J, Pai AA, Nakamura Y, Kurita R, Balasubramanian P, Thangavel S, Marepally S, Velayudhan SR, Srivastava A, Mohankumar KM. Efficient and error-free correction of sickle mutation in human erythroid cells using prime editor-2. Front Genome Ed. 2022 Dec 20;4:1085111. doi: 10.3389/fgeed.2022.1085111. PMID: 36605051; PMCID: PMC9808041.
Bagchi A, Devaraju N, Chambayil K, Rajendiran V, Venkatesan V, Sayed N, Pai AA, Nath A, David E, Nakamura Y, Balasubramanian P, Srivastava A, Thangavel S, Mohankumar KM, Velayudhan SR. Erythroid lineage-specific lentiviral RNAi vectors suitable for molecular functional studies and therapeutic applications. Sci Rep. 2022 Aug 18;12(1):14033. doi: 10.1038/s41598-022-13783-0. PMID: 35982069; PMCID: PMC9388678.
Maddali M, Venkatraman A, Kulkarni UP, Mani S, Raj S, Sigamani E, Korula A, A FN, Lionel SA, Selvarajan S, Manipadam MT, Abraham A, George B, Mathews V, Balasubramanian P. Molecular characterization of triple-negative myeloproliferative neoplasms by next-generation sequencing. Ann Hematol. 2022 Sep;101(9):1987-2000. doi: 10.1007/s00277-022-04920-w. Epub 2022 Jul 15. PMID: 35840818.
Das S, Stallon Illangeswaran RS, Ijee S, Kumar S, Velayudhan SR, Balasubramanian P. Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype. J Vis Exp. 2022 Jun 17;(184):10.3791/63383. doi: 10.3791/63383. PMID: 35786700; PMCID: PMC7614927.
Kulkarni UP, Pai AA, Kavitha ML, Selvarajan S, Lionel S, Devasia AJ, Korula A, Fouzia NA, Sindhuvi E, Abraham A, Srivastava A, Mathews V, George B, Balasubramanian P. Endothelial Activation and Stress Index-Measured Pretransplantation Predicts Transplantation-Related Mortality in Patients with Thalassemia Major Undergoing Transplantation with Thiotepa, Treosulfan, and Fludarabine Conditioning. Transplant Cell Ther. 2022 Jul;28(7):356.e1-356.e6. doi: 10.1016/j.jtct.2022.05.001. Epub 2022 May 9. PMID: 35550442.
Ravi NS, Wienert B, Wyman SK, Bell HW, George A, Mahalingam G, Vu JT, Prasad K, Bandlamudi BP, Devaraju N, Rajendiran V, Syedbasha N, Pai AA, Nakamura Y, Kurita R, Narayanasamy M, Balasubramanian P, Thangavel S, Marepally S, Velayudhan SR, Srivastava A, DeWitt MA, Crossley M, Corn JE, Mohankumar KM. Identification of novel HPFH-like mutations by CRISPR base editing that elevate the expression of fetal hemoglobin. Elife. 2022 Feb 11;11:e65421. doi: 10.7554/eLife.65421. PMID: 35147495; PMCID: PMC8865852.
Kulkarni UP, Selvarajan S, Lionel S, Prakash MA, Palani HK, Balasundaram N, Venkataraman A, Korula A, Devasia AJ, Fouzia NA, Janet NB, Nair SC, Abraham A, Mani T, Lakshmanan J, Arunachalam AK, Balasubramanian P, George B, Mathews V. Real world data with concurrent retinoic acid and arsenic trioxide for the treatment of acute promyelocytic leukemia. Blood Cancer J. 2022 Jan 31;12(1):22. doi: 10.1038/s41408-022-00619-3. PMID: 35102152; PMCID: PMC8803919.
Sathishkumar D, Balasundaram A, Mathew SM, Mathew L, Thomas M, Balasubramanian P, George R. Clinicopathological Profile of Childhood Onset Cutaneous Mastocytosis from a Tertiary Care Center in South India. Indian Dermatol Online J. 2021 Sep 10;12(5):706-713. doi: 10.4103/idoj.IDOJ_924_20. PMID: 34667757; PMCID: PMC8456265.
Pai AA, Mohan A, Benjamin ESB, Illangeswaran RSS, Xavier Raj I, Janet NB, Arunachalam AK, Kavitha ML, Kulkarni U, Devasia AJ, Fouzia NA, Abraham A, Srivastava A, George B, Mathews V, Korula A, Balasubramanian P. NUDT15c.415C>T Polymorphism Predicts 6-MP Induced Early Myelotoxicity in Patients with Acute Lymphoblastic Leukemia Undergoing Maintenance Therapy. Pharmgenomics PersMed. 2021 Oct 2;14:1303-1313. doi: 10.2147/PGPM.S325813. PMID: 34629890; PMCID: PMC8495143.
Balasundaram N, Ganesan S, Chendamarai E, Palani HK, Venkatraman A, Alex AA, David S, Kumar SP, Radhakrishnan NR, Yasar M, Krishna S, Korula A, Kulkarni U, Janet NB, Balasubramanian P, Mathews V. Metabolic adaptation drives arsenictrioxide resistance in acute promyelocytic leukemia. Blood Adv. 2022 Jan 25;6(2):652-663. doi: 10.1182/bloodadvances.2021005300. PMID: 34625794; PMCID: PMC8791572.

Bio data

Education (Post-Graduation onwards & Professional Career)

Degree	University/College	Year	Field of Study
Master of Science (Biochemistry)	Madras University	1990-1992	Clinical Biochemistry
Ph.D. (Biochemistry)	Christian Medical College, Vellore Tamilnadu Dr. MGR Medical University	1995-1999	Biochemistry/Pharmacology-Pharmacokinetics
Post-Doctoral Fellowship	St Jude Children’s Research Hospital Memphis, TN, USA	2007	Pharmaceutical Sciences/Pharmacogenetics
Post-Doctoral Fellowship	University of Chicago	2007 March-September	Pharmacogenetics/Pediatrics

Position and Honors (Position and Employment (Starting with the most recent employment)

University/College	Position	From (Date)	To (date)
Christian Medical College, Vellore	Professor	November 2008	Till date
Christian Medical College, Vellore	Associate Professor	November 2006	November 2008
Christian Medical College, Vellore	Reader	November 2004	November 2006
St Jude Children’s Research Hospital, Memphis, Tennessee-USA	Post-Doctoral Research Associate	September 2004	February 2007
University of Chicago, Chicago, Illinois, USA	Research Professional	March 2007	September 2007