Inactivation of the Suv39h1 Histone Methyltransferase Accelerates Myc-Driven B-Cell Lymphomagenesis and Compromises Drug-Inducible Cellular Senescence.

Activation of the myc oncogene is a frequent finding in human lymphomas. Acute induction of Myc in primary cells initiates massive apoptosis via the ARF/p53 pathway. In turn, apoptotic defects strongly collaborate with Myc in tumor formation. Previous work in a transgenic mouse model demonstrated that DNA damaging drugs can force apoptotically-compromised Myc-lymphomas to enter a terminal cell-cycle arrest, termed cellular senescence, which prolonged overall survival of the tumor-bearing animals. Recently, we identified the histone H3 lysine 9 (H3K9) methyltransferase Suv39h1 as a critical mediator of cellular senescence that acts as an early barrier against Ras-initiated lymphomagenesis, raising the question whether Myc-driven formation of lymphomas and their treatment sensitivity may depend on Suv39h1 function.

Eμ-myc transgenic mice were intercrossed to mice harboring targeted deletions in the Suv39h1 locus. Myc transgenic mice with no additional defined genetic lesions - hereafter referred to as controls - developed B-cell lymphomas with a median onset of more than 100 days, while mice lacking one or both Suv39h1 alleles produced lymphomas significantly earlier, i.e. at a median age of less than 60 days. Importantly, lymphomas arising in female myc transgenic Suv39h1+/− mice invariably lost expression of the X-linked Suv39h1 gene. TUNEL staining in situ and short-term cytotoxicity assays in response to the DNA damaging compound adriamycin in vitro expectedly demonstrated no overt difference in spontaneous or drug-inducible apoptosis in control versus Suv39h1-deficient Myc-lymphomas. However, when the fractions of Myc-driven lymphoma cells in cycle where assessed by Ki67 staining in situ, absence of Suv39h1 allowed Myc to keep nearly all cells in cycle, while a substantial fraction of non-apoptotic control lymphoma cells apparently had exited the cycle. Accordingly, adriamycin-treatment in vitro produced a strong senescent phenotype in control cells in the presence of Bcl2, while no senescence response could be provoked in Suv39h1-deficient cells.

Our findings provide novel insights into Myc-related deregulation of cellular growth control and senescence as a tumor suppressor mechanism, and have important ramifications for the therapeutic utilization of DNA-damage effector programs such as apoptosis and cellular senescence. Whether Suv39h1 inactivation impacts on the long-term outcome of cancer therapy in vivo is currently under investigation and will be reported at the meeting.