Ribosomal lesions promote oncogenic mutagenesis
Congenital ribosomopathies, such as Diamond-Blackfan anemia, are characterized by germline mutations in ribosomal proteins or assembly factors. These patients initially display hypoproliferation of blood lineages, but are also at an increased risk of developing AML and other types of cancer later on. Recently, in hematological malignancies somatic mutations in ribosomal proteins have been described as well. During the Presidential Symposium Dr Sergey Sulima (KU Leuven, Belgium) presented data explaining how a mutated ribosomal protein can promote oncogenic transformation.
In lymphoid mouse cells the ribosomal protein mutation RPL10 R98S, which is found in T cell acute lymphoblastic leukemia (T ALL), resulted in hypoproliferation, which in time was rescued by the accumulation of additional mutations. RPL10 R98S cell lines had a higher mutation rate than wild type cells. Moreover,in these cell lines the investigators observed increased oxidative stress and DNA damage.
A high mutational load was observed as well in T ALL patients with mutations in ribosomal proteins, with enrichment for mutations activating the NOTCH1 pathway. Restoring NOTCH1 expression rescued cells from oxidative stress and promoted cell survival. Similarly, chronic lymphocytic leukemia (CLL) patients with ribosomal protein lesions have a high mutational burden, with enrichment for mutations in TP53.
Sulima: “Ribosome dysfunction increases levels of cellular stress, which inhibits proliferation, but at the same time also promotes mutagenesis. Those mutations that can rescue cells from high oxidative stress get selected for, and can cooperate to drive oncogenesis.”