Role Of Insulin Like Growth Factor mRNA Binding Protein-3 (IGF2BP3) In Mixed Lineage Leukemia (MLL) Positive B-Cell Lymphomas

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3816-3816
Author(s):  
Jayanth Kumar Palanichamy ◽  
Tiffany Tran ◽  
Jorge Contreras ◽  
Thilini R Fernando ◽  
Dinesh S. Rao

Abstract Oncogenic transformation of early B-cell progenitors leads to the human disease of B-acute lymphoblastic leukemia or B-ALL, which affects both children and adults. Among the different subtypes of B-ALL, defined by particular cytogenetic anomalies, there are two which are difficult to treat and have a dismal prognosis. These are B-ALL with chromosomal translocation t (9; 22)/BCR-ABL and MLL gene rearrangements, which show distinctive gene expression profiles. Gene expression is now known to be significantly regulated by post-transcriptional mechanisms. These involve RNA binding proteins and microRNAs. Deregulation of microRNAs as well as RNA binding protein expression is associated with numerous cancers. Here, we hypothesized that RNA binding proteins may be important in regulating gene expression in MLL rearranged leukemias. To examine this hypothesis, we undertook a microarray study examining the expression of both protein-coding and non-coding genes in B-ALL, including MLL translocations. A total of 44 samples were used for the microarray. Supervised class prediction was carried out using the R library of prediction analysis for microarrays (PAM). One of the most significantly differentially expressed genes was Insulin Like Growth Factor mRNA Binding Protein-3 (IGF2BP3). The expression of IGF2BP3 was highest in the MLL rearranged B-ALL group. IGF2BP3 is an oncofetal protein known to be highly expressed in a number of epithelial malignancies such as glioblastomas. IGF2BP3 has been known to bind to the 5’-UTR and stabilize mRNAs like CD44 the expression of which correlates with epithelial tumors metastasis. IGF2BP3 has been shown to bind to the Insulin like Growth Factor-2 (IGF-2) mRNA and enhance translation in glioblastomas. We confirmed the expression of IGF2BP3 and CD44 in these 44 tumor samples and 90 other B-cell lymphoma samples by RT-qPCR. This corroborated with our previous data showing that the expression of both these genes is significantly higher in the group with MLL translocations. In the MLL rearranged leukemias, there was a significant correlation between the expression of CD44 and IGF2BP3. Interestingly however, there was no significant difference in the expression of IGF2 mRNA between these different subsets, indicating either that IGF2BP3 might be acting on IGF-2 mRNA at the translational level or that IGF-2 regulation may be cell-type specific. To evaluate whether IGF2BP3 affects the growth of B-ALL cells, we used NALM6, a B-ALL cell line which expresses IGF2BP3. We generated microRNA-155 formatted siRNAs against human IGF2BP3 and subcloned them into pHAGE6 based lentiviral vectors. Our preliminary data demonstrates that these vectors are capable of knocking down IGF2BP3 in the NALM6 cell line. In addition, cells with knockdown showed a dramatic decrease in their growth rates, as measured by the MTS assay. The IGF-2 paracrine signaling system is thought to be important in the maintenance of HSCs as well as in lymphocyte development. We separated different precursors of B-cells (Hardy fractions) from murine bone marrow using FACS and measured the mRNA expression of CD44 and IGF2BP3 in these different subsets. The expression of both these genes correlated well with each other and showed a dynamic expression pattern with the highest expression seen in the Hardy Fraction C (late pro-B cells). This indicates that the IGF2BP3/CD44 axis might play a role in regulating normal B-cell development and this may be dysregulated in MLL-translocated B-ALL. To examine whether IGF2BP3 overexpression causes leukemia, we cloned the murine and human IGF2BP3 coding regions in a murine retroviral expression vector, MIG (MSCV-IGF2BP3-IRES-GFP). Retroviral packaging was done using 293T cell line, virus was collected and used to infect 7Oz/3, a murine pre-B ALL cell line. Western blot and qPCR confirmed overexpression of IGF2BP3. We have infected bone marrow cells from CD 45.2 positive wild type donor mice with the virus and transferred them into irradiated CD 45.1 recipient mice. We have confirmed engraftment in these mice using flowcytometry for CD 45.1/2 and are presently following the mice for the development of leukemia. In summary, IGF2BP3 is dysregulated in MLL-rearranged leukemia, and its knockdown can cause decreased growth rates in B-ALL cell lines. The current study explores whether IGF2BP3 is oncogenic and the mechanisms of action of IGF2BP3 in B-cell development and neoplasia. Disclosures: No relevant conflicts of interest to declare.

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Junguo Cao ◽  
Qingchun Mu ◽  
Haiyan Huang

RNA-binding proteins (RBPs) mediate the localization, stability, and translation of the target transcripts and fine-tune the physiological functions of the proteins encoded. The insulin-like growth factor (IGF) 2 mRNA-binding protein (IGF2BP, IMP) family comprises three RBPs, IGF2BP1, IGF2BP2, and IGF2BP3, capable of associating with IGF2 and other transcripts and mediating their processing. IGF2BP2 represents the least understood member of this family of RBPs; however, it has been reported to participate in a wide range of physiological processes, such as embryonic development, neuronal differentiation, and metabolism. Its dysregulation is associated with insulin resistance, diabetes, and carcinogenesis and may potentially be a powerful biomarker and candidate target for relevant diseases. This review summarizes the structural features, regulation, and functions of IGF2BP2 and their association with cancer and cancer stem cells.


2004 ◽  
Vol 24 (10) ◽  
pp. 4448-4464 ◽  
Author(s):  
Thomas V. O. Hansen ◽  
Niels A. Hammer ◽  
Jacob Nielsen ◽  
Mette Madsen ◽  
Charlotte Dalbaeck ◽  
...  

ABSTRACT Insulin-like growth factor II mRNA-binding protein 1 (IMP1) belongs to a family of RNA-binding proteins implicated in mRNA localization, turnover, and translational control. Mouse IMP1 is expressed during early development, and an increase in expression occurs around embryonic day 12.5 (E12.5). To characterize the physiological role of IMP1, we generated IMP1-deficient mice carrying a gene trap insertion in the Imp1 gene. Imp1−/− mice were on average 40% smaller than wild-type and heterozygous sex-matched littermates. Growth retardation was apparent from E17.5 and remained permanent into adult life. Moreover, Imp1−/− mice exhibited high perinatal mortality, and only 50% were alive 3 days after birth. In contrast to most other organs, intestinal epithelial cells continue to express IMP1 postnatally, and Imp1−/− mice exhibited impaired development of the intestine, with small and misshapen villi and twisted colon crypts. Analysis of target mRNAs and global expression profiling at E12.5 indicated that Igf2 translation was downregulated, whereas the postnatal intestine showed reduced expression of transcripts encoding extracellular matrix components, such as galectin- 1, lumican, tenascin-C, procollagen transcripts, and the Hsp47 procollagen chaperone. Taken together, the results demonstrate that IMP1 is essential for normal growth and development. Moreover, IMP1 may facilitate intestinal morphogenesis via regulation of extracellular matrix formation.


2010 ◽  
Author(s):  
Christina V. Angeles ◽  
Markus Hafner ◽  
Nicholas D. Socci ◽  
Penelope DeCarolis ◽  
Thomas Tuschl ◽  
...  

2021 ◽  
Vol 22 (13) ◽  
pp. 6940
Author(s):  
Hung-Ming Chen ◽  
Chun-Chi Lin ◽  
Wei-Shone Chen ◽  
Jeng-Kai Jiang ◽  
Shung-Haur Yang ◽  
...  

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an RNA-binding protein and serves as a post-transcriptional fine-tuner regulating the expression of mRNA targets. However, the clinicopathological roles of IGF2BP1 in colorectal cancer (CRC) remains limited. Thus, we aimed to elucidate the clinical significance and biomarker potentials of IGF2BP1 in CRC. A total of 266 specimens from two sets of CRC patients were collected. IGF2BP1 expression was studied by immunohistochemical (IHC) staining. The Kaplan-Meier survival plot and a log-rank test were used for survival analysis. The Cox proportional hazards model was applied to determine the survival impact of IGF2BP1. Public datasets sets from The Cancer Genome Atlas (TCGA) and Human Cancer Metastasis Database (HCMDB), receiver operating characteristic (ROC) plotter, and two CRC cell lines, HCT-116 and DLD-1, were used for validating our findings. We showed that IGF2BP1 was overexpressed in tumor specimens compared to 13 paired normal parts by examining the immunoreactivity of IGF2BP1 (p = 0.045). The increased expression of IGF2BP1 in primary tumor parts was observed regardless of metastatic status (p < 0.001) in HCMDB analysis. IGF2BP1 expression was significantly associated with young age (59.6% vs. 46.7%, p-value = 0.043) and advanced stage (61.3% vs. 40.0%, p-value = 0.001). After controlling for confounding factors, IGF2BP1 remained an independent prognostic factor (HR = 1.705, p-value = 0.005). TCGA datasets analysis indicated that high IGF2BP1 expression showed a lower 5-year survival rate (58% vs. 65%) in CRC patients. The increased expression of IGF2BP1 in chemotherapy non-responder rectal cancer patients was observed using a ROC plotter. Overexpression of IGF2BP1 promoted the colony-forming capacity and 5-fluorouracil and etoposide resistance in CRC cells. Here, IGF2BP1 was an independent poor prognostic marker in CRC patients and contributed to aggressive phenotypes in CRC cell lines.


2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Xinwei Huang ◽  
Hong Zhang ◽  
Xiaoran Guo ◽  
Zongxin Zhu ◽  
Haibo Cai ◽  
...  

2013 ◽  
Vol 69 (2) ◽  
pp. e20-e21
Author(s):  
Chia-Yu Chu ◽  
Yi-Shuan Sheen ◽  
Kuanyin K. Lin ◽  
Meng-Chen Hsieh ◽  
Hsien-Ching Chiu ◽  
...  

2020 ◽  
Vol 10 ◽  
Author(s):  
Caterina Mancarella ◽  
Giulia Caldoni ◽  
Irene Ribolsi ◽  
Alessandro Parra ◽  
Maria Cristina Manara ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document