Cooperativity of IGF2BP1 and ETV6-RUNX1 in the pathogenesis of ETV6- RUNX1 positive B-Cell Acute Lymphoblastic Leukemia Article Swipe
Gunjan Sharma
,
Tiffany Tran
,
Jaspal Bassi
,
Yuan-De Tan
,
Amit Jaiswal
,
Christine Tso
,
Ayushi Jain
,
Jay Singh
,
Anita Chopra
,
Archna Singh
,
Sameer Bakhshi
,
Parthaprasad Chattopadhyay
,
David Casero
,
Dinesh S. Rao
,
Jayanth Kumar Palanichamy
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-1691465/v1
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-1691465/v1
Background ETV6-RUNX1 is the most prevalent translocation in pediatric B-ALL (B-cell Acute Lymphoblastic Leukemia). However, the exact pathogenesis of this translocation leading to leukemogenesis remains unclear. Insulin like Growth Factor 2 Binding Protein 1 (IGF2BP1), an oncofetal RNA binding protein (RBP), is overexpressed in ETV6-RUNX1 positive B-ALL. We intended to investigate the role of IGF2BP1 in leukemogenesis in this study. Methods qRT-PCR was used to analyze IGF2BP1 overexpression in an Indian cohort of pediatric B-ALL ( n = 167 ). IGF2BP1 and ETV6-RUNX1 were knocked out in Reh, an ETV6-RUNX1 positive B-ALL cell line, using CRISPR/Cas9 technology. Cell proliferation assays were used to study cell survival after IGF2BP1 / ETV6-RUNX1 KO and prednisolone response. RNA-Sequencing after IGF2BP1 knockout and RNA Immunoprecipitation sequencing (RIP-Seq) after IGF2BP1 pulldown were performed to find the putative targets of IGF2BP1. Luciferase reporter assays were used to study downstream mRNA target stability as well as pathways regulated by IGF2BP1. Finally, to study the in-vivo synergistic effect between ETV6-RUNX1 fusion protein and IGF2BP1, a murine bone marrow transplant model was utilized followed by flowcytometric analysis of hematopoietic tissues and histopathological examination. Results IGF2BP1 expression was found to be essential for tumor cell survival in Reh cell line. Knockout of IGF2BP1 or ETV6-RUNX1 led to reduced proliferation and increased sensitivity to prednisolone hinting at synergism between both the genes. Integrated analysis of transcriptome sequencing after IGF2BP1 knockout and RIP-Seq revealed that IGF2BP1 targets encompass multiple pro-oncogenic signalling pathways including TNFα/NFκB and PI3K-Akt pathways. Dysregulation of these pathways was also observed in patient samples. Mechanistically, we demonstrate that IGF2BP1 binds and stabilizes ETV6-RUNX1 fusion transcript and the presence of a positive feedback loop between them which maintains a constitutive dysregulation of several oncogenic pathways.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-1691465/v1
- https://www.researchsquare.com/article/rs-1691465/latest.pdf
- OA Status
- green
- References
- 41
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4281628772
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Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4281628772Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.21203/rs.3.rs-1691465/v1Digital Object Identifier
- Title
-
Cooperativity of IGF2BP1 and ETV6-RUNX1 in the pathogenesis of ETV6- RUNX1 positive B-Cell Acute Lymphoblastic LeukemiaWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2022Year of publication
- Publication date
-
2022-05-31Full publication date if available
- Authors
-
Gunjan Sharma, Tiffany Tran, Jaspal Bassi, Yuan-De Tan, Amit Jaiswal, Christine Tso, Ayushi Jain, Jay Singh, Anita Chopra, Archna Singh, Sameer Bakhshi, Parthaprasad Chattopadhyay, David Casero, Dinesh S. Rao, Jayanth Kumar PalanichamyList of authors in order
- Landing page
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https://doi.org/10.21203/rs.3.rs-1691465/v1Publisher landing page
- PDF URL
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https://www.researchsquare.com/article/rs-1691465/latest.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.researchsquare.com/article/rs-1691465/latest.pdfDirect OA link when available
- Concepts
-
Biology, Molecular biology, Cancer research, ETV6, RUNX1, Transcription factor, Gene, Genetics, Chromosomal translocationTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- References (count)
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41Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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