C-terminally truncated form of αB-crystallin is associated with IDH1 R132H mutation in anaplastic astrocytoma

Malignant gliomas are the most common human primary brain tumors. Point mutation of amino acid arginine 132 to histidine (R132H) in the IDH1 protein leads to an enzymatic gain-of-function and is thought to promote gliomagenesis. Little is known about the downstream effects of the IDH1 mutation on protein expression and how and whether changes in protein expression are involved in tumor formation or propagation. In the current study, we used 2D DIGE (difference gel electrophoresis) and mass spectrometry to analyze differences in protein expression between IDH1(R132H) mutant and wild type anaplastic (grade III) astrocytoma from human brain cancer tissues. We show that expression levels of many proteins are altered in IDH1(R132H) mutant anaplastic astrocytoma. Some of the most over-expressed proteins in the mutants include several forms of alpha B-crystallin, a small heat-shock and anti-apoptotic protein. alpha B-crystallin proteins are elevated up to 22-fold in IDH1(R132H) mutant tumors, and alpha B-crystallin expression appears to be controlled at the post-translational level. We identified the most abundant form of alpha B-crystallin as a low molecular weight species that is C-terminally truncated. We also found that overexpression of alpha B-crystallin can be induced by transfecting U251 human glioblastoma cell lines with the IDH1(R132H) mutation. In conclusion, the association of a C-terminally truncated form of alpha B-crystallin protein with the IDH1(R132H) mutation is a novel finding that could impact apoptosis and stress response in IDH1 mutant glioma.