MYBL2: a novel aggressive biomarker in IDH-mutant Astrocytoma

doi:10.21203/rs.3.rs-3809673/v1

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MYBL2: a novel aggressive biomarker in IDH-mutant Astrocytoma

https://doi.org/10.21203/rs.3.rs-3809673/v1

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Purpose:Astrocytoma, IDH-mutant includes CNS WHO grades 2 (A2), 3(A3) and 4(A4). A3 patients have a heterogenous clinical outcome that cannot be fully explained with existing molecular biomarkers. In our previous study we found MYBL2 mRNA to be upregulated in A3 and associated with poor patient outcome. In this study, we aimed to understand the role of MYBL2 in the pathobiology of A3 and clinical course of these patients.

Methods:Protein expression of MYBL2 was investigated on a cohort of A3 and controls using immunohistochemistry (IHC). Its expression was evaluated in paired primary and recurrent samples of A3 and in A2 and A4 tumors. We also assessed p53 immunoreactivity, an important modulator of MYBL2. Functional role of MYBL2 was studied in vitro in three malignant astrocytoma cell-lines [SW1088 and SW783-Secondary cell lines and A3 Primary cell line] using a siRNA knock down approach.

Results:MYBL2 median labelling index (LI) was 15% (0-50%) in A3. Higher MYBL2-LI was associated with shorter PFS (P=0.044) and OS (P=0.017). MYBL2 LI was higher in recurrent tumors compared to primary and in A3 and A4, compared to A2 (P<0.05). p53 LI correlated positively with MYBL2 LI (p=0.026). MYBL2 knockdown was associated with reduced tumor cell proliferation, invasion, and migration.

Conclusion:Our study identified MYBL2 as a novel aggressive biomarker associated with poor prognosis in A3 and with tumor progression. MYBL2 facilitates tumor cell proliferation, migration, and invasion of malignant astrocytoma cells in vitro. Taken together, MYBL2 can be considered as a potentially useful prognostic marker for A3 tumors.

IDH-mutant (IDH-mt.) astrocytomas are a homogenous group of tumors with respect to age at onset, tumor location and molecular alterations such as ATRX and TP53 mutations [1]. However, these tumors are associated with distinct clinical outcomes, with median overall survival (OS) being more than 10 years for Astrocytoma, IDH-mt., CNS WHO grade 2 (A2), 5 to 10 years for Astrocytoma, IDH-mt., CNS WHO grade 3 (A3) and less than three years for Astrocytoma, IDH-mt., CNS WHO grade 4 (A4) [1]. In patients with A2 and A3, the event-free survival is longer but certain genetic and epigenetic modifications within these tumor types have led to rapid disease progression in a subset of patients [2]. Among these, A3 is more heterogeneous and shown to be associated with varied clinical outcomes [3–5]. Our recent study on transcriptome data analysis of A3 tumors identified several differentially expressed genes, of which a few were associated with poor patient prognosis [6]. One such prognostic gene, IRX1, was reported by our group previously [6]. Here, we report another prognostically significant gene, MYBL2, an important oncogene having a role in many systemic cancers including Glioblastoma, IDH-wildtype (GBM) [7–11].

MYBL2 is a member of MYB family of transcription factors. It is a part of the cell cycle pathway and is involved in cell cycle progression [12]. During the S-phase of the cell cycle, cyclin A/ Cyclin-dependent kinase 2 activates MYBL2 protein through phosphorylation. MYBL2 is also a physiological regulator of cell survival and differentiation, and plays a very important role during embryogenesis [13]. Transcriptional mis-regulation of MYBL2 leads to cell proliferation in various cancers [14, 15]. MYBL2 amplification or overexpression is associated with poor patient outcome which has been observed in various systemic cancers [8, 14, 16–19]. In GBM, overexpression of MYBL2 promotes tumor cell proliferation and invasion [11]. However, there are no studies on MYBL2 expression in IDH-mt. astrocytomas.

Our previous study on A3 tumors found MYBL2 mRNA to be up regulated in The Cancer Genome Atlas (TCGA) data analysis. Further, this was validated in our internal cohort of A3 tumors. Survival analysis demonstrated that high levels of MYBL2 mRNA is associated with poor patient prognosis [6]. In continuation with these findings, we aimed to study the protein expression of MYBL2 in our internal cohort of A3 tumors and correlate that with patient prognosis. We assessed the expression of MYBL2 in paired samples and in different grades of IDH-mt. astrocytoma (A2, A3, and A4) and also established its functional role in vitro, using primary and secondary malignant glioma cell lines.

The study had two arms, retrospective and prospective. We had three retrospective data sets, the first of which was an internal cohort of patients with newly diagnosed A3 (n = 100) and control samples, to assess the MYBL2 protein expression and correlate this with patient prognosis. A3 patients included those who underwent surgery from the years 2015–2018 at our institute. Molecular screening (IDH1&2 mutations, ATRX, p53 and CDKN2A/B deletion status) was carried out to derive the cohort, details of which are mentioned in our previous study [6]. The median age of the patients was 35 years (22–67 years) and the median progression free survival (PFS) was 62-months (2–85 months) and overall survival (OS) 71-months (2–87 months). Matched non-neoplastic brain tissue was taken as controls samples (n = 18), and this included tissue from lateral temporal cortex from patients undergoing resective surgery for mesial temporal sclerosis [6]. The second cohort comprised paired samples from both primary (newly diagnosed, A3) and their corresponding recurrent tumour (n = 9) and the third cohort included different grades of IDH-mt. astrocytoma (A2 n = 19, A3 n = 100 and A4 n = 15). MYBL2 expression was studied in these two latter cohorts to evaluate its expression in recurrent tumors compared to the primary and in the different grades. In the prospective arm, biopsy samples of A3 tumor (n = 3) were freshly collected during surgery and one primary cell line which reached the 10th passage was finalized for the functional study (A3.2). In addition, we procured two other cell lines, SW1088 and SW1783 from American Type Culture Collection (ATCC) repository for functional studies.

Immunohistochemistry (IHC):

IHC was performed to assess MYBL2 protein expression using Ventana Benchmark automated staining system (Ventana Benchmark-XT, Ventana Medical Systems, USA) according to the standard protocol. It was run with OptiView HRP multimer staining module and MYBL2 [Sigma, 1:200] primary antibody was used. MYBL2 nuclear staining in tumor cell was assessed. The staining intensity was variable and was graded on a scale of 0 to 2+, where 0 is no staining, 1 + is weak/moderate and 2 + is strong staining, in accordance with our previous reports [6] [20, 21]. Only 2 + staining was considered for labeling index (LI) calculation, as a percentage of 2 + stained tumor cells among the total 2000 of cells that were counted. Staining protocol for p53 is mentioned in our previous report [6].

Transient Knockdown of MYBL2 Using siRNA:

For each assay, cells of all three cell-lines (one primary and two established cell line) were seeded and allowed to grow in complete media for 30 hours, after which the cells were washed, and fresh transfection media (complete media except penstrep) was added. For gene knockdown experiments siRNA (target-MYBL2 and Negative control) and RNA iMAX were prepared with optiMEM solution and incubated at room temperature (RT) for 5 minutes. The siRNA optiMEM and RNA iMax used for each experiment is mentioned in supplementary table (Supplementary Table 1) The mixture was added to the wells/dishes and incubated for 24–30 hours. After transfection, the treated cells were washed with PBS, replenished with fresh media, and allowed to grow for 24 hours. Untreated cells, negative control (NC: siRNA, which is a non-target control in human, mouse, and rat) and MYBL2 knockdown (MYBL2-KD) cell clones were used to assess the mRNA and protein levels after transfection. NC and MYBL2-KD clones were considered for carrying out the functional assays. The details of growing the primary cell-lines, established cell-lines, as well as methodology of immunocytochemistry, functional assays, western blot, quantitative PCR are mentioned in detail in the supplementary document.

Statistical Analysis:

For protein expression study, the LI of protein by IHC was considered for the analysis. Wilcoxon signed-rank test was performed to compare MYBL2 LI between the primary and recurrent tumors in the paired samples analysis. Kruskal-Wallis test was used to compare MYBL2 protein expression in different grades of IDH-mt. astrocytoma. Mann-Whitney U-test was performed to correlate p53 protein expression in high and low MYBL2 expressing group. Survival analysis on the internal(validation) cohort of patients with A3 tumor, was performed using the Cox-regression model. Univariate Cox regression analysis was done to assess the effect of MYBL2 protein expression on PFS and OS of patients, followed by Kaplan-Meier (KM) analysis with log rank test at 95% confidence intervals. For KM analysis, the cohort was divided into two groups: high and low MYBL2 expression groups taking median LI as the cut-off. Median of an event, either tumor recurrence or death of the patient, was calculated in months. For graphical representation of paired sample analysis, in different grades of astrocytomas, and for functional studies Graph pad prism 9.4 version was used.

MYBL2 immunoexpression in internal cohort, paired samples, and different grades of IDH-mt. astrocytoma

In the internal cohort of A3, tumor cells showed variable MYBL2 nuclear staining. The mean LI of the tumor cells was 16.24%±13.56 and median was 15% (0–50%). In the control tissue, the glial cells were negative whereas neurons in the grey matter showed cytoplasmic staining, which was not included for assessment. Staining pattern of the tumor cells and control tissue is shown in Fig. 1.

Paired sample analysis revealed that MYBL2 immunoexpression was significantly higher in recurrent tumors when compared to their corresponding primary tumors (P < 0.05). Median LI of recurrent tumors was 25% (10–30%) as compared to 20% (0–25%) in primary tumors (Fig. 2). A grade-wise analysis of MYBL2 staining pattern showed that MYBL2 expression was higher in A3, and A4 when compared to A2 (P < 0.05), suggesting MYBL2 to be more expressed in higher grades of IDH-mt. astrocytoma (Fig. 2).

MYBL2 association with patient prognosis

Univariate Cox-regression analysis showed that increased MYBL2 labelling was associated with poor PFS with a hazard ratio of 1.032 and p = 0.008, as well as OS with hazard ratio of 1.041 and p = 0.002 in the internal cohort of A3. For KM analysis, this cohort was divided into two groups based on the median LI (15%) i.e., low MYBL2 expressing group (< 15%, n = 51) and high MYBL2 expressing group (≥ 15%, n = 52). We found that the low MYBL2 expressing group was associated with a better PFS when compared with the high expressing group (median: 49 months) and the difference was statistically significant p = 0.044. A similar result was noted with respect to OS with p = 0.017 (Fig. 3a-b).

Correlation of MYBL2 protein expression with its modulator p53.

MYBL2 is known to be present in the downstream of p53 pathway and in p53 mutant cells, it plays an important role in DNA damage as well as escape from G2 arrest. We assessed p53 expression patterns (LI) in both high and low MYBL2 expressing groups and noted that p53 LI was significantly higher in the high-MYBL2 expressing group when compared to low-MYBL2 expressing group (p = 0.026) (Fig. 3c-d).

MYBL2 plays an important role in tumor cell proliferation, invasion, and migration:

MYBL2 functional characterization was carried out using siRNA knockdown approach. We noted that there was significant reduction in MYBL2 mRNA and protein expression in MYBL2-KD when compared to the NC and untreated in all three cell lines, however there was no change in both MYBL2 mRNA and protein expressions when we compared NC and untreated clones, therefore, we used NC and MYBL2-KD for further functional studies (Fig. 4a &b). Cell proliferation analysis in NC and MYBL2-KD clones was assessed using Alamar Blue (AB) method. There was a significant reduction in cell proliferation/viability in MYBL2-KD when compared to the NC in all three cell-lines at a significance of p < 0.05 at all-time points (Fig. 4c). Cell-cycle analysis was performed to understand the phase at which the tumor cells are arrested. We noted that majority of cells were arrested in G2/M phases and also in S phase in MYBL2-KD(Fig. 4d). Wound healing assay was conducted to assess the role of MYBL2 in migration capacity of the tumor cells. In NC, the wound area recovered faster, reducing by 80–90%. However, in MYBL2-KD, the wound recovery was significantly slower, reducing by only 10–20%. This was a statistically significant observation in all three cell-lines [p < 0.001] (Fig. 4e). Tumor cell invasion assay was carried out using the Boyden chamber method for all three cell-lines. We found that there was a reduction in the number of cells that invaded in MYBL2-KD clones when compared to the NC which was statistically significant (P < 0.001), implying that knockdown reduced the invasion capacity of the tumour cells (Fig. 4f).

A3 is a heterogenous group within IDH-mt. astrocytomas due to various co-occurring genomic and epigenomic alterations [22] [2, 3]. Our previous study identified some novel genes, such as IRX1, to be associated with poor prognosis in patients with A3 tumors. We also noted that MYBL2 mRNA expression was up-regulated in A3 when compared to control samples and was significantly associated with poor outcomes [6]. Here, we show that MYBL2 protein expression is high in A3, and associated with poor patient prognosis. Our study is the first of its kind demonstrating the prognostic significance of MYBL2 in IDH-mt. astrocytomas. A previous insilco study on GBM had reported a high expression of MYBL2 in proneural GBM (IDH-mt. grade 4 tumors) [23]. Earlier studies on other cancers such as acute myeloid leukaemia (AML), hepatocellular carcinoma, colorectal carcinoma and breast cancer have also noted that MYBL2 gene is over expressed and is associated with poor patient prognosis [8, 16–18]. We further show higher MYBL2 expression in A3 and A4 when compared to A2 tumors suggesting that it is associated with higher grades of IDH-mt. astrocytoma. Our results are in line with a similar study which reported MYBL2 overexpression in higher grades of glioma (grades III and IV) [11]. We noted that MYBL2 expression was significantly high in recurrent tumors when compared to primary tumors, suggesting that it has a role in tumor progression. This is similar to an in-silico study in CGGA-GBM database which found that MYBL2 expression was high in recurrent when compared to primary GBM samples [24].

Interestingly, breast cancer studies have found that MYBL2 is transcriptionally up-regulated along with other cell cycle related proteins in TP53 mutated tumors [25]. Another study showed MYBL2 and LINC to be downstream molecules of the p53 pathway, playing a very important role in the DNA damage response and that p53 mutant cells require MYBL2 to escape from the G2 checkpoint [26]. In the current study, we noted a significant positive correlation between p53 and MYBL2 expression. Since p53 immunopositivity most often represent the underlying Tp53 mutation, we assume that Tp53 mutation could be responsible for the high MYBL2 expression in IDH-mt. astrocytomas. Previous studies have also found that MYBL2 is a very important member of MMB (LIN9, LIN37, LIN52, LIN53/RBBP4 LIN54, MuvB, and MYBL2) complex in the cell cycle and is not part of DREAM complex (DP, RB-like, E2F, and MuvB, LIN9, LIN37, LIN52, LIN53/RBBP4 and LIN54) which stops cell proliferation, while in the presence of MMB protein, the cells proliferate continuously [27]. We therefore postulate that, in tumor cells, when Tp53 is mutated, it modulates MYBL2 expression and influences association of MYBL2 to form MMB complex, resulting in a continuous expression of MMB complex, thereby escaping the G2 arrest of cell-cycle and resulting in uncontrolled cell proliferation.

Further, to understand the mechanistic action of MYBL2 in tumor cells, we reduced MYBL2 expression using siRNA knockdown approach. Our in-vitro studies showed that MYBL2 significantly contributes to tumour cell proliferation. We observed a significant reduction in cell viability and proliferation in MYBL2-KD clones when compared to NC and very few cells were in G0/G1 phase while majority of cells were arrested either in S or G2/M phase. Similar results were seen when MYBL2 expression in high grade glioma cell lines (U251) was attenuated, the growth ability was greatly reduced and the tumor cells were arrested at G2/M phase of the cell cycle [11] and this was also noted in other cancers such as endometrial carcinoma [28], esophageal squamous-cell carcinoma [10] and non‑small‑cell lung cancer [29]. Studies have shown that cells arrested in G2/M phases usually try to undergo cell repair or apoptosis [30]. It is observed that, when there is a knockdown of MYBL2, the tumor cells get arrested mainly in G2/M phases of the cell cycle, thus explaining reduced proliferation of these cells. In addition, we assessed the invasion and migration capacity of MYBL2-KD cells study and found that MYBL2 is important for tumor cell migration and invasion and is in concordance with other studies on GBM, lung, and colorectal and endometrial cancer [11, 28, 29]. However, it is still uncertain how MYBL2 affects the migration and invasion capacity of cells.

In conclusion, for the first time, we show that MYBL2 is a novel prognostic biomarker of A3 tumors. Also, increased MYBL2 expression is seen in higher grades of IDH-mt. astrocytomas and in recurrent tumors, suggesting its association with tumor progression. This is supported by our in-vitro studies which showed that MYBL2 promotes tumor cell proliferation, migration, and invasion in the context of tumor microenvironment, justifying its aggressive potential. There is a need to further identify the pathways associated with MYBL2 and explore its potential as a therapeutic target.

Acknowledgements: Indian Council of Medical Research is acknowledged for supporting Ms. Harsha S Sugur with ICMR-SRF fellowship. We would like to thank Dr. Yoganand S. M Associate Professor, Department of Biophysics, NIMHANS for his support. We also thank Mr. Chandrashekar, Mr. Suresh for all the technical support. We acknowledge Neurosurgery, Neuropathology and Biostatistics departments of National Institute of Mental Health and Neuro Sciences, Bangalore, India, for providing the necessary samples for conducting the experiment and for helping in data analysis respectively. All the project investigators and members of the Indian Council of Medical Research Ad-hoc project are also acknowledged.

Authors' contributions: Conceptualization: HSS, VS, SR; Methodology: HSS, SG; Formal analysis and investigation: HSS, VS; Writing—original draft preparation: HSS; Writing—review and editing: SR, AA, BP,VS; Funding acquisition: HSS, VS; Resources: AA, BP, VS, SR.

Funding Source: This study was funded by the Indian Council of Medical Research Ad-hoc project (grant no.: No.5/13/80/2020/NCD-III).

Compliance with ethical standards

Conflict of interest: The authors declare that they have no conflict of interest.

Ethical approval: This study has been approved by the Institutional Ethics Committee (NIMH/DO/IEC (BS & NS DIV)/2017-18) and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent: Informed consent was obtained from all individual participants included in the study.

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No competing interests reported.

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MYBL2: a novel aggressive biomarker in IDH-mutant Astrocytoma

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Version 1

Abstract

Figures

Introduction

Material and Methods

Immunohistochemistry (IHC):

Transient Knockdown of MYBL2 Using siRNA:

Statistical Analysis:

Results

MYBL2 association with patient prognosis

MYBL2 plays an important role in tumor cell proliferation, invasion, and migration:

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

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