OLIG2

OLIG2 is well recognized for its importance in cancer research, particularly in brain tumors and leukemia. OLIG2 is universally expressed in glioblastoma and other diffuse gliomas (astrocytomas, oligodendrogliomas and oligoastrocytomas), and is a useful positive diagnostic marker of these brain tumors.[13] Although in normal brain tissue OLIG2 expresses mostly on oligodendrocytes but not on mature astrocytes, in adult glioma, OLIG2 expresses on both IDH1 or IDH2-mutant adult lower grade astrocytoma and oligodendroglioma on similar levels, but it is expressed on a lower level on IDH-wildtype glioblastoma.[14] OLIG2 overexpression is a good surrogate marker for IDH mutation with an AUC of 0.90, but predicts poorly (AUC = 0.55) for 1p/19q co-deletion, a class-defining chromosomal alteration for oligodendroglioma.[14] In survival analysis, higher mRNA levels of OLIG2 were associated with better overall survival, but this association was completely dependent on IDH mutation status.[14]

In particular, OLIG2 is selectively expressed in a subgroup of glioma cells that are highly tumorigenic,[15] and is shown to be required for proliferation of human glioma cells implanted in the brain of severe combined immunodeficiency (SCID) mice.[16]

Though the molecular mechanism behind this tumorigenesis is not entirely clear, more studies have recently been published pinpointing diverse evidence and potential roles for OLIG2 in glioma progression. It is believed that OLIG2 promotes neural stem cell and progenitor cell proliferation by opposing p53 pathway, which potentially contributes to glioma progression. OLIG2 has been shown to directly repress the p53 tumor-suppressor pathway effector p21^WAF1/CIP1,[17] suppress p53 acetylation and impede the binding of p53 to several enhancer sites.[18] It is further found that the phosphorylation of triple-serine motif in OLIG2 is present in several glioma lines and is more tumorigenic than the unphosphorylated status.[19] In a study using the U12-1 cell line for controlled expression of OLIG2, researchers showed that OLIG2 can suppress the proliferation of U12-1 by transactivating the p27^Kip1 gene[20] and can inhibit the motility of the cell by activating RhoA.[21]

Besides glioma, OLIG2 is also involved in leukemogenesis. The Olig2 gene was actually first identified in a study in T-cell acute lymphoblastic leukemia, in which the expression of OLIG2 was found elevated after t(14;21)(q11.2;q22) chromosomal translocation.[22] The overexpression of OLIG2 was later shown present in malignancies beyond glioma and leukemia, such as breast cancer, melanoma and non-small cell lung carcinoma cell lines.[23] It also has been shown that up-regulation of OLIG2 together with LMO1 and Notch1 helps to provide proliferation signals.

OLIG2 is also associated with Down syndrome, as it locates at chromosome 21 within or near the Down syndrome critical region on the long arm. This region is believed to contribute to the cognitive defects of Down syndrome. The substantial increase in the number of forebrain inhibitory neurons often observed in Ts65dn mouse (a murine model of trisomy 21) could lead to imbalance between excitation and inhibition and behavioral abnormalities. However, genetic reduction of OLIG2 and OLIG1 from three copies to two rescued the overproduction of interneurons, indicating the pivotal role of OLIG2 expression level in Down syndrome.[24] The association between OLIG2 and neural diseases (i.e. schizophrenia and Alzheimer’s disease) are under scrutiny, as several single nucleotide polymorphisms (SNPs) associated with these diseases in OLIG2 were identified by genome-wide association work.[25][26]

OLIG2 also plays a functional role in neural repair. Studies showed that the number of OLIG2-expressing cells increased in the lesion after cortical stab-wound injury, supporting the role for OLIG2 in reactive gliosis.[27] OLIG2 was also implicated in generating reactive astrocytes possibly in a transient re-expression manner, but the mechanisms are unclear.[28]