Babal Kant Jha,  Ph.D.

Babal Kant Jha, Ph.D.

Staff Scientist

Principal Investigator

Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195

 

Our research focus is the discovery of cancer cell vulnerabilities to develop novel treatment strategies that protect normal cells and eliminate cancer cells. We are working to develop unique approaches to identify and target malignant cells vulnerabilities. Targeting such vulnerability spare normal cells and provide a restorative therapeutic index. We utilize high throughput screening coupled with iterative structure guided small molecule design, synthesis and pre-clinical in vitro and in vivo characterization of small molecules. We perform pre-clinical drug development and translational feasibility experiments in small animal models. We are interested in understanding the biochemical basis of somatic cell reprograming that modulates anti-tumor immune response. One of the key area of our research focuses on understanding the mechanism of the neoplastic evolution in myeloid malignancies.

Ongoing research projects

Bone marrow failure and associated disorders: mechanism, neoplastic evolution, relapse and therapeutic targeting: Majority of the myeloid malignancies (>95%) are driven by somatic mutations. While somatic mutations drive the oncogenic evolution, they also provide opportunities for targeted therapeutic development. The TET2 gene codes for a DNA-dioxygenase that is frequently affected by loss-of-function mutations (TET2MT) in large proportion of myeloid neoplasia MDS, other myeloid neoplasms including a prodromal state of clonal hematopoiesis of indeterminate potential (CHIP). Prevalence of CHIP are associated with a higher risk for subsequent development of myeloid neoplasia and cardiovascular disorders. TETs (TET1, TET2 and TET3) are Fe2+ and α-ketoglutarate-(αKG)-dependent DNA-dioxygenases, which progressively oxidize 5-methylcyctosine (5mC), in gene promoter and enhancer mCpG-islands. TET dependent oxidation of 5mC ultimately leads to demethylation of mCpG, a critical step for transcription regulation in hematopoietic stem and progenitor cells (HSPC) that determine cell lineage fate, differentiation, proliferation and survival. HSPC harboring TET2MT expand because of their dysregulated differentiation and proliferation programs. TET2 accounts for >1/2 of DNA demethylase activity in HSPC. In TET2 mutant cells, maintenance of minimal TET function (largely by TET3 and to some extent by TET1) is essential for efficient transcription controlling their hyper proliferation and survival. We derived this conclusion from mutual exclusivity of neomorphic IDH1/2MT associated with the production of a weak broad spectrum dioxygenase inhibitor, 2-hydroxyglutarate (2HG) in patients with TET2MT. Thus our hypothesis is: complete or partial loss of TET2 leave affected cells vulnerable to further TET-dioxygenase inhibition primarily coming from TET3 and TET1 e.g., with TET inhibitors (TETi). Therefore, using iterative structure-guided rational design, synthesis and biochemical testing, we developed TETi lead compounds. Our study provided a proof-of-concept to test the hypothesis that TET-inhibition may lead to selective synthetic lethality in TET-deficient/TET2MT malignant cells and may be a new therapeutic paradigm for TET2MT, IDH1/2 mutant and TET dioxygenase deficient cancers. These observations (PMIDs: 31007843, 30709865, 29795413, 32895473, 33681816, 33509440) established our basic hypothesis that TET-dioxygenase deficiency can be a targetable vulnerability in Cancer.

Transient and reversible TET dioxygenase inhibition as a novel therapeutic principle for expansion of normal HSPCs in Aplastic Anemia: As a part of our drug discovery campaign in search of TET-modulators, we discovered that Eltrombopag (Epag), a small molecule thrombopoietin receptor (TPOR) agonist clinically used for the treatment of AA to improve HSC function potently inhibits TET-dioxygenase activity in physiological settings. However, clinically relevant questions including the expansion of stem cell niche, and the refractoriness, in Epag treated AA patients remained unclear. One of the key aspect of Epag function may relate to its off-target mechanism of action, not explained by its known mechanism of actions. For instance, free cellular and extracellular iron (III)-chelating properties of Epag is recently postulated to its biologic effects which may include iron-dependent intracellular pathways in HSC. Recently, we established the TET-inhibitor function of Epag in cell free and cell culture in vitro and in vivo murine models and demonstrated that its HSC function is not related to iron chelation. Based on our analysis of clinical data coupled with biochemical analysis we hypothesize that: i) Epag-mediated inhibition of TET-dioxygenase activity is responsible for tri-lineage response in AA via HSC expansion and on the biochemical level decreased 5hmC content and hypermethylation; ii) direct inhibition of TET2, mimicking LOF mutations, may be responsible for HSC expansion; iii) Inability to inhibit TET2 or/and hypomethylation of target genes is responsible for response failure in some of the patients. The objectives of this proposal will lead to delineation of the mechanism of TET inhibition by Epag and its impact on normal hematopoiesis (https://pubmed.ncbi.nlm.nih.gov/35085104/).These projects are in collaboration with physician scientist Prof. Jaroslaw P Maciejewski, Cleveland Clinic.

ER Stress Response mediated by Protein Disulfide Isomerase PDIA1: A Targetable Vulnerability of Multiple Myeloma Cells.Excessive synthesis and secretion of immunoglobulins which are highly enriched in intra-molecular disulfide bonds compared to any other cell types, is a unique feature of MM. This function, while not linked to the malignant behavior, renders MM cells a great dependence on ER resident PDIA1 that isomerizes cysteine. PDIA1 possess monopoly for rearranging intra-molecular disulfide bonds of membrane and secreted proteins that enter the ER to attain correct folding. Lack of correct folding leads to unfolded protein response that are critical for the survival for MM cells. Therefore, even a partial inhibition of PDIs, disrupts survival of MM cells and may offer help to improve outcomes of patients with MM. While normal cells, including plasma cells also require PDIs to fold disulfide-bridges-containing membrane and secreted proteins, transient PDI inhibition does not overwhelm their ER stress defense due to lower rate of protein turnover and lack of microenvironmental stressors that add to protein misfolding seen in neoplasia. We hypothesize that PDIA1 inhibitor may constitute a novel class of therapeutics with specific activity in MM. Therefore our Objectives are i) Translate anti-MM PDI inhibiting pharmacophores into a drug for relapse and refractory MM; ii) Optimize pharmacologic and PDI inhibiting properties of CCF642 and second generation drugs to maximize its clinical potential in MM.

A novel target and drug to treat chemorefractory AML. Acute myeloid leukemia (AML) is malignant transformation in the myeloid compartment characterized by arrested-differentiation and uncontrolled proliferation of myeloid lineage cells. With current standard-of-care that has as its backbone cytotoxic chemotherapy, 5-year overall survival rates are <40%, and especially poor (5-10%) in AML patients >60 years of age. An exception is for patients with a specific category of AML called acute promyelocytic leukemia (APL), characterized by translocations of the retinoic acid receptor (RARA) and treated with non-cytotoxic differentiation-restoring therapy using a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (AsO3). The most common chromosomal translocation in APL is between chromosome 15 and 17 that creates a leukemia fusion protein PML-RARA. Non-cytotoxic differentiation therapy converted APL from one of the worse prognosis sub-types (when treated with conventional cytotoxic chemotherapy) to currently the disseminated malignancy with the best overall survival outcomes for any disseminated malignancy in man (>90% 5 year survival). Although ATRA is hugely successful in the treatment of APL, its clinical effectiveness in other AML subtypes is very poor. Retinoic acid (RA) is the active metabolite of vitamin A and is the ligand for nuclear receptor transcription factors, e.g., RARA with its heterodimer partner retinoid X receptors (RXRs). RA is also an activating ligand for the peroxisome proliferator-activated receptor β/δ (PPARβ/δ). Functionally, PPAR oppose RARA/RXR, since PPARβ/δ signaling induces transcription of genes that promote proliferation and block terminal differentiation of neoplastic progenitor cells. RA has carrier proteins that transport it in the aqueous intracellular milieu: Cellular Retinoic Acid Binding Protein 2 (CRABP2), and Fatty-Acid-Binding Protein 5 (FABP5), with different cell-types expressing different amounts of these two carriers8. In cells containing high CRABP2/low FABP5, RA activates RARA/RXR resulting in signaling that induces terminal differentiation and growth arrest. On the other hand cells with high FABP5/low CRABP2, RA is preferentially delivered to PPAR β/δ with a resulting promotion of proliferation and differentiation-impediment. Thus, RA carrier proteins are critical determinants of RA signaling and functional outcomes. Our analysis of large databases of AML gene expression revealed that specific AML subtypes contain low CRABP2/high FABP5, leading to our hypothesis: low CRABP2/high FABP5 in certain AMLs channels RA to PPAR to prevent RA-induced terminal-differentiation, and a highly specific inhibitor of FABP5 (FABP5i) may channel back RA to RARA/RXR instead and promote AML terminal-differentiation, to thereby extend the non-cytotoxic therapy benefits of RA to certain AML subtypes other than APL.

Lay Summary

Our lab seeks to understand the basis of cancer evolution. We study genetic and epigenetic dysregulations that promote Cancer and if the very defect that promote Cancer can be exploited for developing therapy. One of the key consideration of our translational research is to protect normal self while restrict and eliminate cancer cell growth.  We are alwasy looking for Talented postdoctoral research fellows commited for translational research. Please contact JHAB@CCF.ORG


Guan Y, Hasipek M, Jiang D, Tiwari AD, Grabowski DR, Pagliuca S, Kongkiatkamon S, Patel B, Singh S, Parker Y, LaFramboise T, Lindner D, Sekeres MA, Mian OY, Saunthararajah Y, Maciejewski JP, Jha BK. Eltrombopag inhibits TET dioxygenase to contribute to hematopoietic stem cell expansion in aplastic anemia. J Clin Invest. 2022 Feb 15;132(4). doi: 10.1172/JCI149856. PubMed PMID: 35085104; PubMed Central PMCID: PMC8843742.

Hasipek M, Grabowski D, Guan Y, Alugubelli RR, Tiwari AD, Gu X, DeAvila GA, Silva AS, Meads MB, Parker Y, Lindner DJ, Saunthararajah Y, Shain KH, Maciejewski JP, Reu FJ, Phillips JG, Jha BK. Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma. Cancers (Basel). 2021 May 28;13(11). doi: 10.3390/cancers13112649. PubMed PMID: 34071205; PubMed Central PMCID: PMC8198550.

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, Jha BK. A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms. Blood Cancer Discov. 2021 Mar;2(2):146-161. doi: 10.1158/2643-3230.BCD-20-0173. Epub 2020 Dec 7. PubMed PMID: 33681816; PubMed Central PMCID: PMC7935131.

Jha BK, Saunthararajah Y. Epigenetic modifier directed therapeutics to unleash healthy genes in unhealthy cells. Semin Hematol. 2021 Jan;58(1):1-3. doi: 10.1053/j.seminhematol.2020.11.009. Epub 2020 Dec 14. PubMed PMID: 33509437; PubMed Central PMCID: PMC8832995.

Guan Y, Hasipek M, Tiwari AD, Maciejewski JP, Jha BK. TET-dioxygenase deficiency in oncogenesis and its targeting for tumor-selective therapeutics. Semin Hematol. 2021 Jan;58(1):27-34. doi: 10.1053/j.seminhematol.2020.12.002. Epub 2020 Dec 28. PubMed PMID: 33509440; PubMed Central PMCID: PMC7938524.

Woerner J, Huang Y, Hutter S, Gurnari C, Sánchez JMH, Wang J, Huang Y, Schnabel D, Aaby M, Xu W, Thorat V, Jiang D, Jha BK, Koyuturk M, Maciejewski JP, Haferlach T, LaFramboise T. Circulating microbial content in myeloid malignancy patients is associated with disease subtypes and patient outcomes. Nat Commun. 2022 Feb 24;13(1):1038. doi: 10.1038/s41467-022-28678-x. PubMed PMID: 35210415.

Gurnari C, Pagliuca S, Guan Y, Adema V, Hershberger CE, Ni Y, Awada H, Kongkiatkamon S, Zawit M, Coutinho DF, Zalcberg IR, Ahn JS, Kim HJ, Kim DDH, Minden MD, Jansen JH, Meggendorfer M, Haferlach C, Jha BK, Haferlach T, Maciejewski JP, Visconte V. TET2 mutations as a part of DNA dioxygenase deficiency in myelodysplastic syndromes. Blood Adv. 2022 Jan 11;6(1):100-107. doi: 10.1182/bloodadvances.2021005418. PubMed PMID: 34768283; PubMed Central PMCID: PMC8753204.

Pagliuca S, Gurnari C, Awada H, Kishtagari A, Kongkiatkamon S, Terkawi L, Zawit M, Guan Y, LaFramboise T, Jha BK, Patel BJ, Hamilton BK, Majhail NS, Lundgren S, Mustjoki S, Saunthararajah Y, Visconte V, Chan TA, Yang CY, Lenz TL, Maciejewski JP. The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders. Blood. 2021 Dec 30;138(26):2781-2798. doi: 10.1182/blood.2021012900. PubMed PMID: 34748628; PubMed Central PMCID: PMC8718627.

Radakovich N, Meggendorfer M, Malcovati L, Hilton CB, Sekeres MA, Shreve J, Rouphail Y, Walter W, Hutter S, Galli A, Pozzi S, Elena C, Padron E, Savona MR, Gerds AT, Mukherjee S, Nagata Y, Komrokji RS, Jha BK, Haferlach C, Maciejewski JP, Haferlach T, Nazha A. A geno-clinical decision model for the diagnosis of myelodysplastic syndromes. Blood Adv. 2021 Nov 9;5(21):4361-4369. doi: 10.1182/bloodadvances.2021004755. PubMed PMID: 34592765; PubMed Central PMCID: PMC8579270.

Gu X, Enane F, Tohme R, Schuerger C, Radivoyevitch T, Parker Y, Zuberi E, Przychodzen B, Jha BK, Lindner D, Rini B, Saunthararajah Y. PBRM1 loss in kidney cancer unbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation. Cell Rep. 2021 Sep 21;36(12):109747. doi: 10.1016/j.celrep.2021.109747. PubMed PMID: 34551289; PubMed Central PMCID: PMC8561673.

Pagliuca S, Gurnari C, Hong S, Zhao R, Kongkiatkamon S, Terkawi L, Zawit M, Guan Y, Awada H, Kishtagari A, Kerr CM, LaFramboise T, Patel BJ, Jha BK, Carraway HE, Visconte V, Majhail NS, Hamilton BK, Maciejewski JP. Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation. JCI Insight. 2021 Jul 8;6(13). doi: 10.1172/jci.insight.149080. PubMed PMID: 34236054; PubMed Central PMCID: PMC8410023.

Tiwari AD, Guan Y, Grabowski DR, Maciejewski JP, Jha BK, Phillips JG. SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates. Bioorg Med Chem. 2021 Jun 1;39:116141. doi: 10.1016/j.bmc.2021.116141. Epub 2021 Apr 20. PubMed PMID: 33894507; PubMed Central PMCID: PMC8171112.

Gu X, Tohme R, Tomlinson B, Sakre N, Hasipek M, Durkin L, Schuerger C, Grabowski D, Zidan AM, Radivoyevitch T, Hong C, Carraway H, Hamilton B, Sobecks R, Patel B, Jha BK, Hsi ED, Maciejewski J, Saunthararajah Y. Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network. Leukemia. 2021 Apr;35(4):1023-1036. doi: 10.1038/s41375-020-1003-x. Epub 2020 Aug 7. PubMed PMID: 32770088; PubMed Central PMCID: PMC7867667.

Khouri J, Faiman BM, Grabowski D, Mahfouz RZ, Khan SN, Wei W, Valent J, Dean R, Samaras C, Jha BK, Lazarus H, Campagnaro EL, Malek E, Reed J, Karam MA, Hamilton K, Fada S, Kalaycio M, Liu H, Sobecks R, Saunthararajah Y, Chew Y, Orloff M, Reu FJ. DNA methylation inhibition in myeloma: Experience from a phase 1b study of low-dose continuous azacitidine in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. Semin Hematol. 2021 Jan;58(1):45-55. doi: 10.1053/j.seminhematol.2020.12.004. Epub 2020 Dec 28. PubMed PMID: 33509443.

Kondratova A, 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 Oct 15;39(20):e106593. doi: 10.15252/embj.2020106593. PubMed PMID: 33058249; PubMed Central PMCID: PMC7560197.

Daou S, Talukdar M, Tang J, Dong B, Banerjee S, Li Y, Duffy NM, Ogunjimi AA, Gaughan C, Jha BK, Gish G, Tavernier N, Mao D, Weiss SR, Huang H, Silverman RH, Sicheri F. A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency. Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):24802-24812. doi: 10.1073/pnas.2006883117. Epub 2020 Sep 21. PubMed PMID: 32958664; PubMed Central PMCID: PMC7547215.

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 Jun 2;39(11):e101573. doi: 10.15252/embj.2019101573. Epub 2020 Apr 23. PubMed PMID: 32323871; PubMed Central PMCID: PMC7265237.

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; PubMed Central PMCID: PMC8673139.

Vargas R, Gopal P, Kuzmishin GB, DeBernardo R, Koyfman SA, Jha BK, Mian OY, Scott J, Adams DJ, Peacock CD, Abazeed ME. Case study: patient-derived clear cell adenocarcinoma xenograft model longitudinally predicts treatment response. NPJ Precis Oncol. 2018;2:14. doi: 10.1038/s41698-018-0060-3. eCollection 2018. PubMed PMID: 30202792; PubMed Central PMCID: PMC6041303.

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.

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.

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.

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.

Chakrabarti A, Jha BK, Silverman RH. New insights into the role of RNase L in innate immunity. J Interferon Cytokine Res. 2011 Jan;31(1):49-57. doi: 10.1089/jir.2010.0120. Epub 2010 Dec 29. Review. PubMed PMID: 21190483; PubMed Central PMCID: PMC3021357.

Yadav G, Prasad RL, Jha BK, Rai V, Bhakuni V, Datta K. Evidence for inhibitory interaction of hyaluronan-binding protein 1 (HABP1/p32/gC1qR) with Streptococcus pneumoniae hyaluronidase. J Biol Chem. 2009 Feb 6;284(6):3897-905. doi: 10.1074/jbc.M804246200. Epub 2008 Nov 11. PubMed PMID: 19004836.

Townsend HL, Jha BK, Silverman RH, Barton DJ. A putative loop E motif and an H-H kissing loop interaction are conserved and functional features in a group C enterovirus RNA that inhibits ribonuclease L. RNA Biol. 2008 Oct-Dec;5(4):263-72. doi: 10.4161/rna.7165. Epub 2008 Oct 9. PubMed PMID: 19088502; PubMed Central PMCID: PMC2953469.

Townsend HL, Jha BK, Han JQ, Maluf NK, Silverman RH, Barton DJ. A viral RNA competitively inhibits the antiviral endoribonuclease domain of RNase L. RNA. 2008 Jun;14(6):1026-36. doi: 10.1261/rna.958908. Epub 2008 Apr 21. PubMed PMID: 18426919; PubMed Central PMCID: PMC2390801.

Washenberger CL, Han JQ, Kechris KJ, Jha BK, Silverman RH, Barton DJ. Hepatitis C virus RNA: dinucleotide frequencies and cleavage by RNase L. Virus Res. 2007 Dec;130(1-2):85-95. doi: 10.1016/j.virusres.2007.05.020. Epub 2007 Jul 2. PubMed PMID: 17604869; PubMed Central PMCID: PMC2186174.

Thakur CS, Jha BK, Dong B, Das Gupta J, Silverman KM, Mao H, Sawai H, Nakamura AO, Banerjee AK, Gudkov A, Silverman RH. Small-molecule activators of RNase L with broad-spectrum antiviral activity. Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9585-90. doi: 10.1073/pnas.0700590104. Epub 2007 May 29. PubMed PMID: 17535916; PubMed Central PMCID: PMC1877983.

Han JQ, Townsend HL, Jha BK, Paranjape JM, Silverman RH, Barton DJ. A phylogenetically conserved RNA structure in the poliovirus open reading frame inhibits the antiviral endoribonuclease RNase L. J Virol. 2007 Jun;81(11):5561-72. doi: 10.1128/JVI.01857-06. Epub 2007 Mar 7. PubMed PMID: 17344297; PubMed Central PMCID: PMC1900262.

Andersen JB, Li XL, Judge CS, Zhou A, Jha BK, Shelby S, Zhou L, Silverman RH, Hassel BA. Role of 2-5A-dependent RNase-L in senescence and longevity. Oncogene. 2007 May 10;26(21):3081-8. doi: 10.1038/sj.onc.1210111. Epub 2006 Nov 20. PubMed PMID: 17130839.

Molinaro RJ, Jha BK, Malathi K, Varambally S, Chinnaiyan AM, Silverman RH. Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells. Nucleic Acids Res. 2006;34(22):6684-95. doi: 10.1093/nar/gkl968. Epub 2006 Dec 1. PubMed PMID: 17145707; PubMed Central PMCID: PMC1751551.

Jha BK, Salunke DM, Datta K. Hyaluronan Structure and Function. In: Balaz EA, Hascall VC, editors. Hyaluronan [Internet] 1 ed. Edgewater, New Jersey 07020, USA: Matrix Biology Institute; 2005. Chapter 3; p.89-92. 950p. Available from: https://www.matrixbio.org/.

Jha BK, Mitra N, Rana R, Surolia A, Salunke DM, Datta K. pH and cation-induced thermodynamic stability of human hyaluronan binding protein 1 regulates its hyaluronan affinity. J Biol Chem. 2004 May 28;279(22):23061-72. doi: 10.1074/jbc.M310676200. Epub 2004 Mar 5. PubMed PMID: 15004022.

Jha BK, Salunke DM, Datta K. Structural flexibility of multifunctional HABP1 may be important for regulating its binding to different ligands. J Biol Chem. 2003 Jul 25;278(30):27464-72. doi: 10.1074/jbc.M206696200. Epub 2003 Apr 27. PubMed PMID: 12719421.

Jha BK, Salunke DM, Datta K. Disulfide bond formation through Cys186 facilitates functionally relevant dimerization of trimeric hyaluronan-binding protein 1 (HABP1)/p32/gC1qR. Eur J Biochem. 2002 Jan;269(1):298-306. doi: 10.1046/j.0014-2956.2001.02654.x. PubMed PMID: 11784324.

Deb TB, Majumdar M, Bharadwaj A, Jha BK, Datta K. An insight into cellular signaling mediated by hyaluronan binding protein (HABP1).. In: Kennedy JF, Phillips GO, Williams PA, Hascall VC, editors. Hyaluronan [Internet] 1 ed. England: Woodhead Publishing; 2000. Chapter 45; p.365-372. 1152p. Available from: https://www.elsevier.com/books/hyaluronan/kennedy/978-1-85573-570-5.

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


05/19/2022 |  

Researchers Find Potential for Repurposing Drug to Target Certain Types of Leukemia Cells

Drs. Jha and Maciejewski have identified eltrombopag as a potent inhibitor of specific leukemia cells, which could lead to new drugs that target leukemia cells while preserving and expanding normal blood cells.




12/11/2020 |  

Cancer Researchers Identify Potential New Class of Drugs to Treat Blood and Bone Marrow Cancers

Drs. Maciejewski and Jha developed a small molecule that selectively targeted and effectively eliminated cancer cells with a certain genetic mutation in preclinical models of myeloid leukemia, while simultaneously granting survival advantage to healthy cells.