Genomic instability in mouse Burkitt lymphoma is dominated by illegitimate genetic recombinations, not point mutations.

in Oncogene by Lynne D Rockwood, Ted A Torrey, Joong Su Kim, Allen E Coleman, Alexander L Kovalchuk, Shao Xiang, Thomas Ried, Herbert C Morse, Siegfried Janz

TLDR

  • The study found that MYC-induced mouse Burkitt lymphoma exhibits genomic instability characterized by illegitimate genetic rearrangements, rather than a hypermutability phenotype.
  • The results suggest that lymphomagenesis can occur through mechanisms other than hypermutability, and that cellular selection of advantageous mutations may be a key factor.

Abstract

lambda-MYC-induced mouse Burkitt lymphoma (BL) harboring the shuttle vector pUR288, which includes a lacZ reporter gene to study mutagenesis, was employed to assess genomic instability associated with MYC deregulation. The frequency of lacZ mutations in lymphomas was elevated only 1.75-fold above that in normal tissue, indicating that mouse BL does not exhibit a phenotype of hypermutability. However, the nature of lacZ mutations was strikingly different in normal tissues and lymphomas. While point mutations comprised approximately 75% of the mutations found in normal tissues, apparent translocations, deletions and inversions constituted the majority of mutations ( approximately 65%) in lymphomas. Genomic instability in mouse BL thus seems characterized by a preponderance of illegitimate genetic rearrangements in the context of near-background mutant frequencies. SKY analyses of cell lines from primary BL tumors revealed substantial changes in chromosomal structure, confirming the lacZ studies. Bi-allelic deletions of the tumor suppressor p16(Ink4a) were detected in six out of 16 cell lines, illustrating cellular selection of advantageous mutations. Together, these approaches indicate that MYC may contribute to lymphomagenesis through the dominant mutator effect of inducing chromosomal instability. The results further suggest that a phenotype of hypermutability (elevated mutant frequency) may not always be required for oncogenesis to occur.

Overview

  • The study employed a mouse Burkitt lymphoma (BL) model to investigate genomic instability associated with MYC deregulation.
  • The model used a lacZ reporter gene to study mutagenesis in lymphomas and normal tissues.
  • The primary objective was to determine the role of MYC in lymphomagenesis and whether it induces a hypermutability phenotype.

Comparative Analysis & Findings

  • The frequency of lacZ mutations in lymphomas was elevated only 1.75-fold above that in normal tissue, indicating a near-background mutant frequency.
  • The nature of lacZ mutations was strikingly different in normal tissues and lymphomas, with point mutations being rare in lymphomas but frequent in normal tissues.
  • Genomic instability in mouse BL was characterized by a preponderance of illegitimate genetic rearrangements, including apparent translocations, deletions, and inversions.

Implications and Future Directions

  • The study suggests that MYC may contribute to lymphomagenesis through the dominant mutator effect of inducing chromosomal instability, rather than a hypermutability phenotype.
  • The findings hint that cellular selection of advantageous mutations may play a crucial role in oncogenesis, which can occur through mechanisms other than hypermutability.
  • Future studies could investigate the specific types of chromosomal rearrangements induced by MYC deregulation and their potential roles in lymphomagenesis.
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