Institute seminar April 7th 10.30
The institute seminar on Wednesday April 7th is given by Trond Stokke from the Department of Radiation Biology.
Title of his talk:
B-cell Non-Hodgkin’s lymphomas – from in vivo genotypes to cell cycle arrest phenotypes in vitro
The seminar takes place in the Auditorium (New Research Building Montebello) and starts at 10:30.
We have studied genotypes and phenotypes of primary malignant B-cell Non-Hodgkin’s lymphomas in a panel of about hundred cases. Lymphoma-characteristic translocations, mutations, homogeneous and heterogeneous copy number aberrations were studied employing techniques like comparative genome hybridization (CGH), array-CGH, FISH, and long-range PCR. Assuming that the heterogeneous aberrations were the last ones, we could deduce the order of genomic events during lymphomagenesis, and whether clonal evolution occurred in a sequential or parallel fashion. Multivariate studies of survival showed that losses of TP53 and ATM, as well as gains on 6p, predicted a poor survival (in addition to the International prognostic index, IPI). However, S phase fraction still had marginal significance, indicating that other genomic aberrations driving proliferation have not been identified in our studies.
To supplement these descriptive in vivo studies, the roles of TP53 and ATM, as well as other proteins in the relevant pathways, in checkpoints in the cell cycle have been further studied in cell lines in vitro. DNA double-strand breaks were introduced by ionizing radiation, and inhibitors and siRNA’s were employed to inactivate or knock down specific proteins to reveal their role in the arrest prior to S phase and mitosis. Both TP53 and ATM are involved in the arrest at both checkpoints, but with a different interrelationship, as they seem to work in the same pathway upstream of the G1-S checkpoint, but in independent pathways upstream of the G2-M checkpoint. There is also a third independent molecular pathway upstream of the G2-M checkpoint, employing e.g. ATR and CHEK1, but this pathway is seldom found to be abrogated in tumors, probably because at least ATR is essential for cell survival. These results may provide an explanation for why TP53 and ATM have independent prognostic value in primary tumors, but do not show a clear negative association. Molecular pathway-specific treatment strategies for the future will be briefly discussed.