Inhibition of the intrinsic but not the extrinsic apoptosis pathway accelerates and drives MYC-driven tumorigenesis towards acute myeloid leukemia.

• Main Authors: Kari Högstrand, Eduar Hejll, Birgitta Sander, Björn Rozell, Lars-Gunnar Larsson, Alf Grandien
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2012-01-01
• Series: PLoS ONE
• Online Access: http://europepmc.org/articles/PMC3290626?pdf=render

Myc plays an important role in tumor development, including acute myeloid leukemia (AML). However, MYC is also a powerful inducer of apoptosis, which is one of the major failsafe programs to prevent cancer development. To clarify the relative importance of the extrinsic (death receptor-mediated) versus the intrinsic (mitochondrial) pathway of apoptosis in MYC-driven AML, we coexpressed MYC together with anti-apoptotic proteins of relevance for AML; BCL-X(L)/BCL-2 (inhibiting the intrinsic pathway) or FLIP(L) (inhibiting the extrinsic pathway), in hematopoietic stems cells (HSCs). Transplantation of HSCs expressing MYC into syngeneic recipient mice resulted in development of AML and T-cell lymphomas within 7-9 weeks as expected. Importantly, coexpression of MYC together with BCL-X(L)/BCL-2 resulted in strongly accelerated kinetics and favored tumor development towards aggressive AML. In contrast, coexpression of MYC and FLIP(L) did neither accelerate tumorigenesis nor change the ratio of AML versus T-cell lymphoma. However, a change in distribution of immature CD4(+)CD8(+) versus mature CD4(+) T-cell lymphoma was observed in MYC/FLIP(L) mice, possibly as a result of increased survival of the CD4+ population, but this did not significantly affect the outcome of the disease. In conclusion, our findings provide direct evidence that BCL-X(L) and BCL-2 but not FLIP(L) acts in synergy with MYC to drive AML development.