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

Abstract

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.

• Authors: Kari Högstrand, Eduar Hejll, Birgitta Sander, Björn Rozell, Lars-Gunnar Larsson, Alf Grandien
• Journal: PloS one (PLoS One) Vol. 7 Issue 2 Pg. e31366 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22393362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Proteins
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Cflar protein, mouse
• Luminescent Proteins
• MYC protein, human
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• bcl-X Protein
• yellow fluorescent protein, Bacteria
• Green Fluorescent Proteins

Topics

• Animals
• Apoptosis
• Bacterial Proteins (metabolism)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Female
• Gene Expression Regulation, Leukemic
• Green Fluorescent Proteins (metabolism)
• Hematopoietic Stem Cells (cytology)
• Humans
• Kinetics
• Leukemia, Myeloid, Acute (metabolism)
• Luminescent Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred DBA
• Models, Biological
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• bcl-X Protein (metabolism)