Babal Kant Jha,  Ph.D.

Babal Kant Jha, Ph.D.

Project Staff

Principal Investigator

Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195
Location: NE6-305

Phone: (216) 444-6739

 

Epigenetics play a critical role in every cell to mount an accurate and efficient transcription profile for the maintenance of tissue-specific gene expression patterns to regulate normal development. The epigenetic dysregulation leads to genomic instability and aberrant gene expression that promotes decoupling of proliferation and differentiation a root cause of neoplastic evolution. Perturbation in one or more components of the epigenetic machinery (DNA methylation/demethylation, histone modifications, nucleosome positioning) driven by somatic or germline mutations are in the center of neoplastic evolution. The major interest of our research is to understand the distinct alterations in the epigenetic landscape that occur in cancer compared with normal cells. We investigate the role of DNA base modifications in the promoter and enhancer segments in cancer initiation and progression.The reversible nature of epigenetic aberrations has led us to develop novel treatment strategy by preferential targeting of malignant cells.Somatic mutations are essential pathogenic lesions in myeloid neoplasia. Among a variety of genes affected, some mutations can serve as target for drug development either directly or through modulation of down/up-stream pathways and regulatory signaling networks critical for leukemic cell survival and proliferation. DNA methylation-demethylation is central to epigenetic gene regulation. In humans, 60–80% of CpGs are methylated in somatic cells as a default state. TET-dioxygenases serve as the erasers of methylation from CpG containing DNA with TET2 accounting for more than 50% of TET activity in hematopoietic stem and progenitor cells (HSPCs). Somatic mutations in the TET2 gene (TET2MT) are one of the most common genetic defects in myeloid neoplasia. Recently, we found that the loss of function mutations in TET2 a major DNA dioxygenase in myeloid leukemia leads to their susceptibility towards further TET inhibition. TET2MT cause partial loss of dioxygenase catalyzed oxidation of 5-methyl cytosine (5mC)à 5hydroxy methyl cytosine (5hmC) à5-formyl cytosine à (5fC) à5-carboxyl cytosine (caC) and hence regulate the promoter and enhancer activity.

We have developed a potent small molecule TET inhibitor which induced synthetic lethality to TET deficient pro-leukemic cells. TET-dioxygenase inhibition in TET-deficient leukemic cells leads to apoptosis.

Understanding structure-function relationship at atomic levels to discover new therapeutic targets and medicine of future has been the focus of our research over a decade. We are looking into ways by which HSC dysfunction happens and if that can be targeted for therapeutic development.

Lay Summary

Our lab seeks to understand how epegenetic dysregulation promotes neoplastic evolution and if the very defect that promote neoplasia can be targeted for novel therapeutic strategies.


Guan Y, Tiwari AD,  Phillips JG, Hasipek M,  Grabowski DR, Pagliuca S, Gopal P, Kerr CM, Adema V, Radivoyevitch T, Parker Y, Lindner DJ, Meggendorfer M,  Abazeed M, Sekeres MA, Mian OY, Haferlach T, Maciejewski JP and Jha BK (2020). A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms. bloodcandisc.0173.2020. doi:10.1158/2643-3230.BCD-20-0173 %J Blood Cancer Discovery

Guan Y, Greenberg EF, Hasipek M, Chen S, Liu X, Kerr CM, Gackowski D, Zarakowska E, Radivoyevitch T, Gu X, Willard B, Visconte V, Makishima H, Nazha A, Mukherji M, Sekeres MA, Saunthararajah Y, Oliński R, Xu M, Maciejewski JP, Jha BK. Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia. Commun Biol. 2020 Sep 7;3(1):493. doi: 10.1038/s42003-020-01220-9. PubMed PMID: 32895473; PubMed Central PMCID: PMC7477582.

Kondratova AA, Cheon H, Dong B, Holvey-Bates EG, Hasipek M, Taran I, Gaughan C, Jha BK, Silverman RH, Stark GR. Suppressing PARylation by 2',5'-oligoadenylate synthetase 1 inhibits DNA damage-induced cell death. EMBO J. 2020 Apr 23;:e101573. doi: 10.15252/embj.2019101573. [Epub ahead of print] PubMed PMID: 32323871.

Kuzmanovic T, Patel BJ, Sanikommu SR, Nagata Y, Awada H, Kerr CM, Przychodzen BP, Jha BK, Hiwase D, Singhal D, Advani AS, Nazha A, Gerds AT, Carraway HE, Sekeres MA, Mukherjee S, Maciejewski JP, Radivoyevitch T. Genomics of therapy-related myeloid neoplasms. Haematologica. 2020 Mar;105(3):e98-e101. doi: 10.3324/haematol.2019.219352. Epub 2019 Aug 14. PubMed PMID: 31413096; PubMed Central PMCID: PMC7049337.

Mulkearns-Hubert EE, Torre-Healy LA, Silver DJ, Eurich JT, Bayik D, Serbinowski E, Hitomi M, Zhou J, Przychodzen B, Zhang R, Sprowls SA, Hale JS, Alban TJ, Berezovsky A, Bell BA, Lockman PR, Jha BK, Lathia JD. Development of a Cx46 Targeting Strategy for Cancer Stem Cells. Cell Rep. 2019 Apr 23;27(4):1062-1072.e5. doi: 10.1016/j.celrep.2019.03.079. PubMed PMID: 31018124; PubMed Central PMCID: PMC6497083.

Kishtagari A, Jha BK, Maciejewski JP. TET2 mutations and clonal dynamics. Oncotarget. 2019 Mar 12;10(21):2010-2011. doi: 10.18632/oncotarget.26779. eCollection 2019 Mar 12. PubMed PMID: 31007843; PubMed Central PMCID: PMC6459340.

Awada H, Nagata Y, Goyal A, Asad MF, Patel B, Hirsch CM, Kuzmanovic T, Guan Y, Przychodzen BP, Aly M, Adema V, Shen W, Williams L, Nazha A, Abazeed ME, Sekeres MA, Radivoyevitch T, Haferlach T, Jha BK, Visconte V, Maciejewski JP. Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia. Blood Adv. 2019 Feb 12;3(3):339-349. doi: 10.1182/bloodadvances.2018024216. PubMed PMID: 30709865; PubMed Central PMCID: PMC6373752.

Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, Shima H, Aly M, Pastor V, Kuzmanovic T, Radivoyevitch T, Adema V, Awada H, Yoshida K, Li S, Sole F, Hanna R, Jha BK, LaFramboise T, Ogawa S, Sekeres MA, Wlodarski MW, Cammenga J, Maciejewski JP. Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes. Blood. 2018 Nov 22;132(21):2309-2313. doi: 10.1182/blood-2017-05-787390. Epub 2018 Oct 15. PubMed PMID: 30322869; PubMed Central PMCID: PMC6251008.

Gu X, Ebrahem Q, Mahfouz RZ, Hasipek M, Enane F, Radivoyevitch T, Rapin N, Przychodzen B, Hu Z, Balusu R, Cotta CV, Wald D, Argueta C, Landesman Y, Martelli MP, Falini B, Carraway H, Porse BT, Maciejewski J, Jha BK, Saunthararajah Y. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates. J Clin Invest. 2018 Oct 1;128(10):4260-4279. doi: 10.1172/JCI97117. Epub 2018 Jul 17. PubMed PMID: 30015632; PubMed Central PMCID: PMC6159976.

Hirsch CM, Nazha A, Kneen K, Abazeed ME, Meggendorfer M, Przychodzen BP, Nadarajah N, Adema V, Nagata Y, Goyal A, Awada H, Asad MF, Visconte V, Guan Y, Sekeres MA, Olinski R, Jha BK, LaFramboise T, Radivoyevitch T, Haferlach T, Maciejewski JP. Consequences of mutant TET2 on clonality and subclonal hierarchy. Leukemia. 2018 Aug;32(8):1751-1761. doi: 10.1038/s41375-018-0150-9. Epub 2018 May 24. PubMed PMID: 29795413.

Drappier M, Jha BK, Stone S, Elliott R, Zhang R, Vertommen D, Weiss SR, Silverman RH, Michiels T. A novel mechanism of RNase L inhibition: Theiler's virus L* protein prevents 2-5A from binding to RNase L. PLoS Pathog. 2018 Apr;14(4):e1006989. doi: 10.1371/journal.ppat.1006989. eCollection 2018 Apr. PubMed PMID: 29652922; PubMed Central PMCID: PMC5927464.

Goldstein SA, Thornbrough JM, Zhang R, Jha BK, Li Y, Elliott R, Quiroz-Figueroa K, Chen AI, Silverman RH, Weiss SR. Lineage A Betacoronavirus NS2 Proteins and the Homologous Torovirus Berne pp1a Carboxy-Terminal Domain Are Phosphodiesterases That Antagonize Activation of RNase L. J Virol. 2017 Mar 1;91(5). doi: 10.1128/JVI.02201-16. Print 2017 Mar 1. PubMed PMID: 28003490; PubMed Central PMCID: PMC5309944.

Vatolin S, Phillips JG, Jha BK, Govindgari S, Hu J, Grabowski D, Parker Y, Lindner DJ, Zhong F, Distelhorst CW, Smith MR, Cotta C, Xu Y, Chilakala S, Kuang RR, Tall S, Reu FJ. Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma. Cancer Res. 2016 Jun 1;76(11):3340-50. doi: 10.1158/0008-5472.CAN-15-3099. Epub 2016 Apr 6. PubMed PMID: 27197150.

Sui B, Huang J, Jha BK, Yin P, Zhou M, Fu ZF, Silverman RH, Weiss SR, Peng G, Zhao L. Crystal structure of the mouse hepatitis virus ns2 phosphodiesterase domain that antagonizes RNase L activation. J Gen Virol. 2016 Apr;97(4):880-886. doi: 10.1099/jgv.0.000395. Epub 2016 Jan 11. PubMed PMID: 26757803; PubMed Central PMCID: PMC5974288.

Thornbrough JM, Jha BK, Yount B, Goldstein SA, Li Y, Elliott R, Sims AC, Baric RS, Silverman RH, Weiss SR. Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation. mBio. 2016 Mar 29;7(2):e00258. doi: 10.1128/mBio.00258-16. PubMed PMID: 27025250; PubMed Central PMCID: PMC4817253.

Ogden KM, Hu L, Jha BK, Sankaran B, Weiss SR, Silverman RH, Patton JT, Prasad BV. Structural basis for 2'-5'-oligoadenylate binding and enzyme activity of a viral RNase L antagonist. J Virol. 2015 Jul;89(13):6633-45. doi: 10.1128/JVI.00701-15. PubMed PMID: 25878106; PubMed Central PMCID: PMC4468480.

Gusho E, Zhang R, Jha BK, Thornbrough JM, Dong B, Gaughan C, Elliott R, Weiss SR, Silverman RH. Murine AKAP7 has a 2',5'-phosphodiesterase domain that can complement an inactive murine coronavirus ns2 gene. mBio. 2014 Jul 1;5(4):e01312-14. doi: 10.1128/mBio.01312-14. PubMed PMID: 24987090; PubMed Central PMCID: PMC4161237.

Agyeman A, Jha BK, Mazumdar T, Houghton JA. Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding. Oncotarget. 2014 Jun 30;5(12):4492-503. doi: 10.18632/oncotarget.2046. PubMed PMID: 24962990; PubMed Central PMCID: PMC4147340.

Cooper DA, Jha BK, Silverman RH, Hesselberth JR, Barton DJ. Ribonuclease L and metal-ion-independent endoribonuclease cleavage sites in host and viral RNAs. Nucleic Acids Res. 2014 Apr;42(8):5202-16. doi: 10.1093/nar/gku118. Epub 2014 Feb 5. PubMed PMID: 24500209; PubMed Central PMCID: PMC4005677.

Banerjee S, Chakrabarti A, Jha BK, Weiss SR, Silverman RH. Cell-type-specific effects of RNase L on viral induction of beta interferon. mBio. 2014 Feb 25;5(2):e00856-14. doi: 10.1128/mBio.00856-14. PubMed PMID: 24570368; PubMed Central PMCID: PMC3940032.

Huang H, Zeqiraj E, Dong B, Jha BK, Duffy NM, Orlicky S, Thevakumaran N, Talukdar M, Pillon MC, Ceccarelli DF, Wan LC, Juang YC, Mao DY, Gaughan C, Brinton MA, Perelygin AA, Kourinov I, Guarné A, Silverman RH, Sicheri F. Dimeric structure of pseudokinase RNase L bound to 2-5A reveals a basis for interferon-induced antiviral activity. Mol Cell. 2014 Jan 23;53(2):221-34. doi: 10.1016/j.molcel.2013.12.025. PubMed PMID: 24462203; PubMed Central PMCID: PMC3974923.

Zhou Y, Kang MJ, Jha BK, Silverman RH, Lee CG, Elias JA. Role of ribonuclease L in viral pathogen-associated molecular pattern/influenza virus and cigarette smoke-induced inflammation and remodeling. J Immunol. 2013 Sep 1;191(5):2637-46. doi: 10.4049/jimmunol.1300082. Epub 2013 Aug 2. PubMed PMID: 23913960; PubMed Central PMCID: PMC3750064.

Jha BK, Dong B, Nguyen CT, Polyakova I, Silverman RH. Suppression of antiviral innate immunity by sunitinib enhances oncolytic virotherapy. Mol Ther. 2013 Sep;21(9):1749-57. doi: 10.1038/mt.2013.112. Epub 2013 Jun 4. PubMed PMID: 23732991; PubMed Central PMCID: PMC3776628.

Zhang R, Jha BK, Ogden KM, Dong B, Zhao L, Elliott R, Patton JT, Silverman RH, Weiss SR. Homologous 2',5'-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity. Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13114-9. doi: 10.1073/pnas.1306917110. Epub 2013 Jul 22. PubMed PMID: 23878220; PubMed Central PMCID: PMC3740845.

Sorgeloos F, Jha BK, Silverman RH, Michiels T. Evasion of antiviral innate immunity by Theiler's virus L* protein through direct inhibition of RNase L. PLoS Pathog. 2013;9(6):e1003474. doi: 10.1371/journal.ppat.1003474. Epub 2013 Jun 27. PubMed PMID: 23825954; PubMed Central PMCID: PMC3694852.

Mohan ML, Jha BK, Gupta MK, Vasudevan NT, Martelli EE, Mosinski JD, Naga Prasad SV. Phosphoinositide 3-kinase γ inhibits cardiac GSK-3 independently of Akt. Sci Signal. 2013 Jan 22;6(259):ra4. doi: 10.1126/scisignal.2003308. PubMed PMID: 23354687; PubMed Central PMCID: PMC3967506.

Zhao L, Jha BK, Wu A, Elliott R, Ziebuhr J, Gorbalenya AE, Silverman RH, Weiss SR. Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology. Cell Host Microbe. 2012 Jun 14;11(6):607-16. doi: 10.1016/j.chom.2012.04.011. PubMed PMID: 22704621; PubMed Central PMCID: PMC3377938.

Schuessler A, Funk A, Lazear HM, Cooper DA, Torres S, Daffis S, Jha BK, Kumagai Y, Takeuchi O, Hertzog P, Silverman R, Akira S, Barton DJ, Diamond MS, Khromykh AA. West Nile virus noncoding subgenomic RNA contributes to viral evasion of the type I interferon-mediated antiviral response. J Virol. 2012 May;86(10):5708-18. doi: 10.1128/JVI.00207-12. Epub 2012 Feb 29. PubMed PMID: 22379089; PubMed Central PMCID: PMC3347305.

Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):E869-78. doi: 10.1073/pnas.1115623109. Epub 2012 Feb 6. PubMed PMID: 22315414; PubMed Central PMCID: PMC3326519.

Keel AY, Jha BK, Kieft JS. Structural architecture of an RNA that competitively inhibits RNase L. RNA. 2012 Jan;18(1):88-99. doi: 10.1261/rna.030007.111. Epub 2011 Nov 23. PubMed PMID: 22114318; PubMed Central PMCID: PMC3261747.

Anderson BR, Muramatsu H, Jha BK, Silverman RH, Weissman D, Karikó K. Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L. Nucleic Acids Res. 2011 Nov;39(21):9329-38. doi: 10.1093/nar/gkr586. Epub 2011 Aug 3. PubMed PMID: 21813458; PubMed Central PMCID: PMC3241635.

 Jha BK, Polyakova I, Kessler P, Dong B, Dickerman B, Sen GC, Silverman RH. Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity. J Biol Chem. 2011 Jul 29;286(30):26319-26. doi: 10.1074/jbc.M111.253443. Epub 2011 Jun 2. PubMed PMID: 21636578; PubMed Central PMCID: PMC3143594.

 Elbahesh H, Jha BK, Silverman RH, Scherbik SV, Brinton MA. The Flvr-encoded murine oligoadenylate synthetase 1b (Oas1b) suppresses 2-5A synthesis in intact cells. Virology. 2011 Jan 20;409(2):262-70. doi: 10.1016/j.virol.2010.10.016. Epub 2010 Nov 5. PubMed PMID: 21056894; PubMed Central PMCID: PMC3046042.

Complete list: https://www.ncbi.nlm.nih.gov/myncbi/1pagsdBbcpM/bibliography/public/


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