Dr. Pulikkan completed his PhD from Ludwig Maximilian University of Munich, Germany. His work elucidated the first direct mechanism by which C/EBPα regulates cell cycle control in hematopoiesis and provided strong evidence that restoration of microRNA levels could be a novel therapeutic avenue in cancer.
For his post-doctoral research, Dr. Pulikkan joined the University of Massachusetts Medical School. He co-discovered AI-10-49, a small molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC, which is associated with inv(16) leukemia. This work provided proof-of-principle that protein-protein interactions and oncogenic transcription factors, so-called “undruggable” targets in cancer therapy can be effectively targeted by small molecule inhibitors. Currently, AI-10-49 is under development as an anti-leukemic drug. In a follow-up study, Dr. Pulikkan showed that pharmacologic inhibition of the CBFβ-SMMHC/RUNX1 interaction by AI-10-49 leads to RUNX1-mediated changes in MYC enhancer chromatin dynamics, which in turn results in inhibition of the MYC transcriptional program and apoptosis. This study brought novel insights on how cancer driver mutations ‘hijack’ chromatin dynamics through deregulating the SWI/SNF chromatin remodeling complex/ Polycomb repressive complex (PRC) axis.
Dr. Pulikkan’s outstanding achievements during his post-doctoral research have been recognized by several awards, including the American Society of Hematology (ASH) Scholar Award, Alex's Lemonade Stand Foundation Young Investigator Award, Lauri Strauss Leukemia Foundation Discovery Grant and UMASS Cancer Center researcher award. During his doctoral research Dr. Pulikkan was awarded the German José Carreras Leukemia Foundation Research Fellowship, Wilhelm Roux Research Scholarship and Daimler Benz Foundation Research Fellowship.
Dr. Pulikkan’s laboratory focuses on deciphering the interplay between transcription factors and chromatin dynamics in normal and malignant hematopoietic stem cells, and understanding the function of non-coding RNAs in myeloid development and leukemia. The long-term goal of the Pulikkan lab is to identify and characterize novel therapeutic targets, and translate them to the clinic for leukemia treatment.
Chromatin dynamics and gene regulation in normal and malignant hematopoiesis
Acute myeloid leukemia (AML) and several hematological malignancies arise from acquisition of multiple stepwise genetic and epigenetic changes in hematopoietic stem and progenitor cells. Understanding the regulatory pathways that are deregulated in hematopoietic stem and progenitor cells is important to better understand the development of leukemia and to design novel therapeutic strategies for the treatment of leukemia. With that broad focus in mind, our lab applies genetic, epigenetic and biochemical approaches in genetically modified mouse models, humanized mouse models and human primary leukemic cells. Our research focus on three areas:
- Interplay between transcription factors and chromatin dynamics in normal and malignant HSCs
The development of chromosome conformation capture technology has revolutionized our understanding of long-range enhancer-promoter interactions and how these interactions are deregulated in multiple diseases. However, our understanding of chromatin structure and how transcription factors regulate higher-order genome architecture is limited. We are exploring the mechanisms by which transcription factors regulate chromatin dynamics in normal and malignant HSCs, and the implications of chromosomal rearrangements observed in hematological malignancies in topologically associated domains (TAD) architecture and gene expression.
- Transcriptional deregulation in AML
Mutations in transcription factors have long been shown to be central in tumorigenesis. Our lab is interested in understanding transcriptional regulation of myeloid differentiation and how this is altered in AML. In particular, we are studying deregulation of transcription factors C/EBPα and core-binding factors, CBFs (consisting of RUNX and CBFβ proteins) in AML. We are investigating the preleukemic molecular events in AML with CEBPA mutations and chromosomally rearranged RUNX1/ CBFβ.
- Non-coding RNA function in hematopoiesis and leukemia
While around 76% of the human genome is transcribed into RNA, only 2% of the genome is translated to proteins. Recent findings in RNA biology made a paradigm shift in our understanding of RNA function beyond acting as templates for protein synthesis. An emerging theme in gene regulation is the central role played by long non-coding RNAs (lncRNAs). We are interested in understanding the functional relevance of deregulated lncRNAs in AML with altered CBF and C/EBPα activity and the therapeutic relevance of targeting lncRNAs in AML treatment.
(Pulikkan JA, Hegde M, Ahmad HM, Belaghzal H, Illendula A, Yu J, O'Hagan K, Ou J, Muller-Tidow C, Wolfe SA, Zhu LJ, Dekker J, Bushweller JH, Castilla LH.) Cell. 2018 06 28;174(1):172-186.e21.
(Pulikkan JA, Castilla LH.) Front Oncol. 2018;8:129.
(Illendula A, Gilmour J, Grembecka J, Tirumala VSS, Boulton A, Kuntimaddi A, Schmidt C, Wang L, Pulikkan JA, Zong H, Parlak M, Kuscu C, Pickin A, Zhou Y, Gao Y, Mishra L, Adli M, Castilla LH, Rajewski RA, Janes KA, Guzman ML, Bonifer C, Bushweller JH.) EBioMedicine. 2017 11;25:188.
(Pulikkan JA, Tenen DG, Behre G.) Leukemia. 2017 11;31(11):2279-2285.
(Choi A, Illendula A, Pulikkan JA, Roderick JE, Tesell J, Yu J, Hermance N, Zhu LJ, Castilla LH, Bushweller JH, Kelliher MA.) Blood. 2017 10 12;130(15):1722-1733.
(Illendula A, Gilmour J, Grembecka J, Tirumala VSS, Boulton A, Kuntimaddi A, Schmidt C, Wang L, Pulikkan JA, Zong H, Parlak M, Kuscu C, Pickin A, Zhou Y, Gao Y, Mishra L, Adli M, Castilla LH, Rajewski RA, Janes KA, Guzman ML, Bonifer C, Bushweller JH.) EBioMedicine. 2016 Jun;8:117-131.
(Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L, Sen S, Zhou Y, Boulton A, Kuntimaddi A, Gao Y, Rajewski RA, Guzman ML, Castilla LH, Bushweller JH.) Science. 2015 Feb 13;347(6223):779-84.
(Xue L, Pulikkan JA, Valk PJ, Castilla LH.) Blood. 2014 Jul 17;124(3):426-36.
(Pulikkan JA, Madera D, Xue L, Bradley P, Landrette SF, Kuo YH, Abbas S, Zhu LJ, Valk P, Castilla LH.) Blood. 2012 Jul 26;120(4):868-79.
(Pulikkan JA, Peramangalam PS, Dengler V, Ho PA, Preudhomme C, Meshinchi S, Christopeit M, Nibourel O, Müller-Tidow C, Bohlander SK, Tenen DG, Behre G.) Blood. 2010 Dec 16;116(25):5638-49.
(Pulikkan JA, Dengler V, Peer Zada AA, Kawasaki A, Geletu M, Pasalic Z, Bohlander SK, Ryo A, Tenen DG, Behre G.) Leukemia. 2010 May;24(5):914-23.
(Pulikkan JA, Dengler V, Peramangalam PS, Peer Zada AA, Müller-Tidow C, Bohlander SK, Tenen DG, Behre G.) Blood. 2010 Mar 04;115(9):1768-78.