Diagnostic Utility of IGF2BP1 and Its Targets as Potential Biomarkers in ETV6-RUNX1 Positive B-Cell Acute Lymphoblastic Leukemia

Sharma, Gunjan; Boby, Elza; Nidhi, Thakur; Jain, Ayushi; Singh, Jay; Singh, Archna; Chattopadhyay, Parthaprasad; Bakhshi, Sameer; Chopra, Anita; Palanichamy, Jayanth Kumar

doi:10.3389/fonc.2021.588101

Cited by 9 publications

(6 citation statements)

References 45 publications

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“…We had earlier reported the overexpression of IGF2BP1 by RT-qPCR in the bone marrow of patients belonging to the ETV6::RUNX1 subtype in a cohort of Indian patients ( n =114) [ 28 ]. Additional samples were added to the same cohort (Total n =167).…”

Section: Resultsmentioning

confidence: 99%

“…Cdkn2a loss , alterations of Epor, Ebf1, Jak1, Jak3, Il2rb, Stat5 and Trp53 have all been shown to synergize with ETV6::RUNX1 to cause leukemia in mice [ 10 , 42 , 43 , 47 ]. We had previously identified that the RBP IGF2BP1 was specifically overexpressed in the ETV6::RUNX1 translocated B-ALL and validated the same in a larger cohort [ 28 ]. The importance of RBPs in the pathogenesis of various leukemias including the IGF2BP family is slowly being dissected [ 48 ].…”

Section: Discussionmentioning

confidence: 96%

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

Sharma,

Tran,

Bansal

et al. 2023

J Exp Clin Cancer Res

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Background Acute 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. Methods Gene 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. Results We 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. Conclusion Our 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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

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

Sharma,

Tran,

Bansal

et al. 2023

J Exp Clin Cancer Res

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“…Discontinuation of L-asparaginase and poor response to prednisolone is associated with poor outcomes in ETV6::RUNX1-positive pediatric B-ALL patients, indicating drug insensitivity [53]. Autophagy inhibition [54], spleen tyrosine kinase (SYK) [55], and IGF2BP1 [56] are potential future therapeutic targets for ETV6::RUNX1-driven B-cell precursor acute lymphoblastic leukemia due to their roles in ETV6::RUNX1 cell survival and prognosis. Through RNA-seq, we can identify upregulated and activated pathways at diagnosis and design combination chemotherapeutics to sensitize resistant primary cells to conventional drugs.…”

Section: Discussionmentioning

confidence: 99%

The potential role of RNA sequencing in diagnosing unexplained insensitivity to conventional chemotherapy in pediatric patients with B-cell acute lymphoblastic leukemia

Li,

Huang,

Zhu

et al. 2024

BMC Med Genomics

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Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be divided into more than 10 subgroups. However, many genomic defects associated with resistance mechanisms have not yet been identified. As an individual clinical tool for molecular diagnostic risk classification, RNA-seq and gene expression pattern-based therapy could be potential upcoming strategies. In this study, we retrospectively analyzed the RNA-seq gene expression profiles of 45 children whose molecular diagnostic classifications were inconsistent with the response to chemotherapy. The relationship between the transcriptome and chemotherapy response was analyzed. Fusion gene identification was conducted for the included patients who did not have known high-risk associated fusion genes or gene mutations. The most frequently detected fusion gene pair in the high-risk group was the DHRSX duplication, which is a novel finding. Fusions involving ABL1, LMNB2, NFATC1, PAX5, and TTYH3 at onset were more frequently detected in the high-risk group, while fusions involving LFNG, TTYH3, and NFATC1 were frequently detected in the relapse group. According to the pathways involved, the underlying drug resistance mechanism is related to DNA methylation, autophagy, and protein metabolism. Overall, the implementation of an RNA-seq diagnostic system will identify activated markers associated with chemotherapy response, and guide future treatment adjustments.

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“…Clinically, a previous study reveals that EGFL7 serves as a potential diagnostic marker in B-cell acute lymphoblastic leukemia (B-ALL) patients [17]. Another recent study displays that EGFL7 is overexpressed in AML patients compared to controls, and its overexpression relates to lower complete remission rates in AML patients [8].…”

Section: Discussionmentioning

confidence: 99%

Relation among EGFL7, ITGB3, and KLF2 and their clinical implication in multiple myeloma patients: a prospective study

Zhang

Gong

2021

Ir J Med Sci

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Objective We aimed to investigate the relationship among epidermal growth factor–like protein-7 (EGFL7), integrin subunit beta 3 (ITGB3), and Kruppel-like factor 2 (KLF2) expressions and their clinical implication in multiple myeloma (MM). Methods This prospective study enrolled 72 de novo symptomatic MM patients and 30 controls, and then collected their bone marrow plasma cell samples. Subsequently, the EGFL7, ITGB3, and KLF2 expressions were carried out by reverse transcription quantitative polymerase chain reaction. Results EGFL7, ITGB3, and KLF2 expressions were increased in MM patients compared to controls. Besides, EGFL7, ITGB3, and KLF2 inter-correlated with each other in MM patients but not in controls. In MM patients, EGFL7 and ITGB3 (but not KLF2) expressions were positively correlated with ISS stage, while ITGB3 and KLF2 (but not EGFL7) expressions were correlated with increased R-ISS stage. Interestingly, ITGB3 and KLF2 were decreased in induction-treatment complete remission (CR) MM patients compared to non-CR MM patients, while EGFL7 only showed a trend but without statistical significance. Furthermore, ITGB3 high expression was correlated with worse progression-free survival (PFS) and overall survival (OS), while EGFL7 and KLF2 high expressions only associated with pejorative PFS but not OS. Conclusion EGFL7, ITGB3, and KLF2 may serve as potential prognostic indicators in MM patients.

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Diagnostic Utility of IGF2BP1 and Its Targets as Potential Biomarkers in ETV6-RUNX1 Positive B-Cell Acute Lymphoblastic Leukemia

Cited by 9 publications

References 45 publications

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

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

The potential role of RNA sequencing in diagnosing unexplained insensitivity to conventional chemotherapy in pediatric patients with B-cell acute lymphoblastic leukemia

Relation among EGFL7, ITGB3, and KLF2 and their clinical implication in multiple myeloma patients: a prospective study

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