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12. RNA binding protein IGF2BP1 synergizes with ETV6-RUNX1 to drive oncogenic signaling in B-cell Acute Lymphoblastic Leukemia

Author

Sharma, Gunjan, Tran, Tiffany M, Bansal, Ishu, Beg, Mohammad Sabique, Bhardwaj, Ruchi, Bassi, Jaspal, Tan, Yuande, Jaiswal, Amit Kumar, Tso, Christine, Jain, Ayushi, Singh, Jay, Chattopadhyay, Parthaprasad, Singh, Archna, Chopra, Anita, Bakhshi, Sameer, Casero, David, Rao, Dinesh S, and Palanichamy, Jayanth Kumar

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pediatric Cancer, Human Genome, Rare Diseases, Cancer, Hematology, Pediatric, Genetics, Biotechnology, Stem Cell Research, Aetiology, 2.1 Biological and endogenous factors, Animals, Mice, Core Binding Factor Alpha 2 Subunit, Mice, Knockout, Phosphatidylinositol 3-Kinases, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cell Lymphoblastic Leukemia-Lymphoma, ETS Translocation Variant 6 Protein, RNA binding protein, Leukemia, ETV6::RUNX1 translocation, B-ALL, NF kappa B, PI3K pathways, NFκB, Oncology and carcinogenesis
Abstract

BackgroundAcute lymphoblastic leukemia (ALL) is the most common pediatric hematological malignancy, with ETV6::RUNX1 being the most prevalent translocation whose exact pathogenesis remains unclear. IGF2BP1 (Insulin-like Growth Factor 2 Binding Protein 1) is an oncofetal RNA binding protein seen to be specifically overexpressed in ETV6::RUNX1 positive B-ALL. In this study, we have studied the mechanistic role of IGF2BP1 in leukemogenesis and its synergism with the ETV6::RUNX1 fusion protein.MethodsGene expression was analyzed from patient bone marrow RNA using Real Time RT-qPCR. Knockout cell lines were created using CRISPR-Cas9 based lentiviral vectors. RNA-Seq and RNA Immunoprecipitation sequencing (RIP-Seq) after IGF2BP1 pulldown were performed using the Illumina platform. Mouse experiments were done by retroviral overexpression of donor HSCs followed by lethal irradiation of recipients using a bone marrow transplant model.ResultsWe observed specific overexpression of IGF2BP1 in ETV6::RUNX1 positive patients in an Indian cohort of pediatric ALL (n=167) with a positive correlation with prednisolone resistance. IGF2BP1 expression was essential for tumor cell survival in multiple ETV6::RUNX1 positive B-ALL cell lines. Integrated analysis of transcriptome sequencing after IGF2BP1 knockout and RIP-Seq after IGF2BP1 pulldown in Reh cell line revealed that IGF2BP1 targets encompass multiple pro-oncogenic signalling pathways including TNFα/NFκB and PI3K-Akt pathways. These pathways were also dysregulated in primary ETV6::RUNX1 positive B-ALL patient samples from our center as well as in public B-ALL patient datasets. IGF2BP1 showed binding and stabilization of the ETV6::RUNX1 fusion transcript itself. This positive feedback loop led to constitutive dysregulation of several oncogenic pathways. Enforced co-expression of ETV6::RUNX1 and IGF2BP1 in mouse bone marrow resulted in marrow hypercellularity which was characterized by multi-lineage progenitor expansion and strong Ki67 positivity. This pre-leukemic phenotype confirmed their synergism in-vivo. Clonal expansion of cells overexpressing both ETV6::RUNX1 and IGF2BP1 was clearly observed. These mice also developed splenomegaly indicating extramedullary hematopoiesis.ConclusionOur data suggest a combined impact of the ETV6::RUNX1 fusion protein and RNA binding protein, IGF2BP1 in activating multiple oncogenic pathways in B-ALL which makes IGF2BP1 and these pathways as attractive therapeutic targets and biomarkers.

Published
2023

13. Prognostic relevance of surface expression of cytokine receptor-like factor 2 in pediatric B-lineage acute lymphoblastic leukemia.

Author

Singh, Jay, Benjamin, Mercilena, Pandey, Avanish, Kumari, Sarita, Ali, Mohammad, Palanichamy, Jayanth, Bakhshi, Sameer, Singh, Amitabh, Pushpam, Deepam, Kumar, Akash, Seth, Rachna, Singh, Inder, Tanwar, Pranay, Singh, Amar, Arora, Mohit, Chopra, Anita, and Sharma, Gunjan

Subjects
B-ALL, CRLF2, Leukemia, copy number alterations, pediatric malignancies, prognosis
Abstract

Overexpression of cytokine receptor-like factor 2 (CRLF2) resulting from its genomic rearrangement is the most frequent genetic alteration found in Philadelphia chromosome-like (Ph-like) B-cell acute lymphoblastic leukemia (B-ALL), a high-risk leukemia. Detection of CRLF2 expression by multiparameter flow cytometry has been proposed as a screening tool for the identification of Ph-like B-ALL. However, the prognostic relevance of flow cytometric expression of CRLF2 in pediatric B-ALL is not very clear. Additionally, its association with common copy number alterations (CNA) has not been studied in detail. Hence, in this study, we prospectively evaluated the flow cytometric expression of CRLF2 in 256 pediatric B-ALL patients and determined its association with molecular features such as common CNAs detected using Multiplex ligation-dependent probe amplification and mutations in CRLF2, JAK2 and IL7RA genes. Further, its association with clinicopathological features including patient outcome was assessed. We found that 8.59% (22/256) pediatric B-ALL patients were CRLF2-positive at diagnosis. Among CNAs, CRLF2 positivity was associated with presence of PAX5 alteration (P=0.041). JAK2 and IL-7R mutations were found in 9% and 13.6% CRLF2-positive patients, respectively. IGH::CRLF2 or P2RY8::CRLF2 fusions were each found in 1/22 individuals. CRLF2-positive patients were found to have inferior overall (hazard ratio (HR) =4.39, P=0.006) and event free survival (HR=2.62, P=0.045), independent to other clinical features. Furthermore, concomitant CNA of IKZF1 in CRLF2 positive patients was associated with a greater hazard for poor overall and event free survival, compared to patients without these alterations or presence of any one of them. Our findings demonstrate that the surface CRLF2 expression in association with IKZF1 copy number alteration can be used to risk stratify pediatric B-ALL patients.

Published
2023

25. Ubiquitin specific peptidase 37 and PCNA interaction promotes osteosarcoma pathogenesis by modulating replication fork progression

Author

Chauhan, Ravi, Gupta, Ashna, Malhotra, Lakshay, Bhat, Ajaz A., Pandita, Raj K., Masoodi, Tariq, Dagar, Gunjan, Sadida, Hana Q., Al-Marzooqi, Sara K., Batra, Atul, Bakhshi, Sameer, Sharma, Mehar Chand, Tanwar, Pranay, Khan, Shah Alam, Samath, Ethayathulla Abdul, Uddin, Shahab, Akil, Ammira S. Al-Shabeeb, Haris, Mohammad, Macha, Muzafar A., Pandita, Tej K., and Singh, Mayank

Published
2023
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30. Prognostic significance of PD-1/PD-L1 expression in uveal melanoma: correlation with tumor-infiltrating lymphocytes and clinicopathological parameters.

Author

Singh, Lata, Singh, Mithalesh, Kenney, Maria, Jager, Martine, Rizvi, Moshahid, Meel, Rachna, Lomi, Neiwete, Bakhshi, Sameer, Sen, Seema, and Kashyap, Seema

Subjects
Immunotherapy, Interferon gamma, Tumor-infiltrating lymphocytes, Uveal melanoma, B7-H1 Antigen, Cell Line, Tumor, Cell Movement, Eye Neoplasms, Follow-Up Studies, Humans, Immunohistochemistry, Immunotherapy, Interferon-gamma, Lymphocytes, Tumor-Infiltrating, Melanoma, Polymerase Chain Reaction, Prognosis, Programmed Cell Death 1 Receptor, Survival Analysis, Uveal Neoplasms
Abstract

BACKGROUND: To understand how to improve the effect of immune checkpoint inhibitors in uveal melanoma (UM), we need a better understanding of the expression of PD-1 and PD-L1, their relation with the presence of tumor-infiltrating lymphocytes (TILs), and their prognostic relevance in UM patients. MATERIALS AND METHODS: Expression of PD-1 and PD-L1 was assessed in 71 UM tissue samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR), and further validated by western blotting. The effect of interferon gamma (IFN-γ) on PD-1/PD-L1 expression was determined on four UM cell lines. RESULTS: Immunoreactivity of PD-1 was found in 30/71 cases and of PD-L1 in 44/71 UM samples. Tumor-infiltrating lymphocytes were found in 46% of UM tissues. PD-1 was expressed on TILs while tumor cells expressed PD-L1. UM with and without TILs showed expression of PD-1 in 69% and 18% cases, respectively (p = 0.001). Similarly, PD-L1 was found in 75% of UM with TILs and in 50% of cases without TILs, respectively (p = 0.03). DFS rate were lower in patients with TILs with expression of PD-1 and PD-L1, but the rate of DFS was higher with expression of PD-L1 in patients without TILs. After treatment of UM cell lines with IFN-γ, PD-1 expression was induced in all UM cell lines whereas PD-L1 expression was found at a lower level in untreated cells, while expression also increased following treatment with IFN-γ. CONCLUSION: Our study suggests that increased infiltration with TILs promotes the aggressive behavior and suppresses the immune response of UM cells, thereby inhibiting immunotherapy.

Published
2021

35. Looking beyond toxicities: Other health-related morbidities noted in childhood solid tumor survivors

Author

Sehgal, Mehak, Jain, Vishesh, Agarwala, Sandeep, Dhua, Anjan, Goel, Prabudh, Yadav, Devendra, Bakhshi, Sameer, and Kalaivani, Mani

Subjects
Health, Pediatrics, Tumors, Health
Abstract

Byline: Mehak. Sehgal, Vishesh. Jain, Sandeep. Agarwala, Anjan. Dhua, Prabudh. Goel, Devendra. Yadav, Sameer. Bakhshi, Mani. Kalaivani Aim: In addition to the well-known toxicities of treatment, survivors of pediatric solid [...]

Published
2023

39. Synergistic Hypoxia and Apoptosis Conditioning Unleashes Superior Mesenchymal Stem Cells Efficacy in Acute Graft-versus-Host-Disease

Author

Mendiratta, Mohini, primary, Mendiratta, Meenakshi, additional, Ganguly, Shuvadeep Kumar, additional, Rai, Sandeep, additional, Gupta, Ritu, additional, Kumar, Lalit, additional, Bakhshi, Sameer, additional, Dadhwal, Vatsla, additional, Pushpam, Deepam, additional, Malik, Prabhat S, additional, Pramanik, Raja, additional, Aggarwal, Mukul, additional, Gupta, Aditya Kumar, additional, Dhawan, Rishi, additional, Seth, Tulika, additional, Mahapatra, Manoranjan, additional, Nayak, Baibaswata, additional, Singh, Thoudam Debraj, additional, Singla, Sachin Kumar, additional, Singh, Mayank, additional, Prasad, Chandra Prakash, additional, Prakash, Hridayesh, additional, Mohanty, Sujata, additional, and Sahoo, Ranjit Kumar, additional

Published
2024
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42. COVID-19 infection, and reinfection, and vaccine effectiveness against symptomatic infection among health care workers in the setting of omicron variant transmission in New Delhi, India

Author

Malhotra, Sumit, Mani, Kalaivani, Lodha, Rakesh, Bakhshi, Sameer, Mathur, Vijay Prakash, Gupta, Pooja, Kedia, Saurabh, Sankar, Mari Jeeva, Kumar, Parmeshwar, Kumar, Arvind, H, Vikas, Ahuja, Vineet, Sinha, Subrata, Guleria, Randeep, Dua, Aman, Ahmad, Shafi, Upadhyay, Ashish Datt, Sati, Hem Chandra, Mani, Kiruba, Lokade, Amol Kumar, Devi, K. Pavithra, Johnson, Riya Marie, Gowthaman, Keerthana, Kumari, Mamta, Singh, Ritika, Kalra, Devanshi, Swetambri, Vasudha, Sharma, Shubhangi, Singh, Amit, Sharma, Vikas, Kanswal, Sunita, Sharma, Rahul, Giri, Tanika, Rajput, Simple, Mehra, Geeta, Sharma, Amit, Madan, Divya, Singh, Mukesh, Gupta, Anvita, Sharma, Shilpi, Sachdeva, Surbhi, Kumar, Mayank, Sachin, Singh, Ajay Kumar, Gohar, Naveen, Kumar, Ramu, Kanojia, Nitin, Singhania, Jyoti, Dubey, Ritu, Shukla, Sakshi, G, Abishek, Sarkar, Swarnabha, Gupta, Ishan, Rai, Sabin, Tummala, Snikitha, Reddy, Thrisha, Vadodaria, Vishwa, Sharma, Ajay, Gupta, Amit, Vats, Manish, Deori, Trideep Jyoti, Jaiswal, Abhishek, and Pandit, Sabitri

Published
2022
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44. Effect of Prior Therapy and Disease Refractoriness on the Efficacy and Safety of Oral Selinexor in Patients with Diffuse Large B-cell Lymphoma (DLBCL): A Post-hoc Analysis of the SADAL Study

Author

Schuster, Michael, Zijlstra, Josée, Casasnovas, Rene-Olivier, Vermaat, Joost S.P, Kalakonda, Nagesh, Goy, Andre, Choquet, Sylvain, Neste, Eric Van Den, Hill, Brian, Thieblemont, Catherine, Cavallo, Federica, De la Cruz, Fatima, Kuruvilla, John, Hamad, Nada, Jaeger, Ulrich, Caimi, Paolo, Gurion, Ronit, Warzocha, Krzysztof, Bakhshi, Sameer, Sancho, Juan-Manuel, Follows, George, Egyed, Miklos, Offner, Fritz, Vassilakopoulos, Theodoros, Samal, Priyanka, Ku, Matthew, Ma, Xiwen, Corona, Kelly, Chamoun, Kamal, Shah, Jatin, Shacham, Sharon, Kauffman, Michael G., Canales, Miguel, and Maerevoet, Marie

Published
2022
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49. Protocol for ICiCLe-ALL-14 (InPOG-ALL-15-01): a prospective, risk stratified, randomised, multicentre, open label, controlled therapeutic trial for newly diagnosed childhood acute lymphoblastic leukaemia in India

Author

Das, Nandana, Banavali, Shripad, Bakhshi, Sameer, Trehan, Amita, Radhakrishnan, Venkatraman, Seth, Rachna, Arora, Brijesh, Narula, Gaurav, Sinha, Subir, Roy, Prakriti, Gogoi, Manash Pratim, Chatterjee, Sayan, Abraham, Bindhu, Das, Parag, Saha, Vaskar, and Krishnan, Shekhar

Published
2022
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