Molecular Pathogenesis of Chromosome 16 Inversion AML

Liu, Pu Paul

Abstract

Chromosome 16 inversion is one of the most common chromosome abnormalities in human acute myeloid leukemia. A fusion gene between the core binding factor B (CBFB) gene and the myosin heavy chain 11 (MYH11) gene is generated by this inversion. Using transgenic mouse models we demonstrated recently that CBFB-MYH11 is necessary but not sufficient for leukemogenesis, and that additional genetic changes are needed for full leukemic transformation. We have since been able to identify such cooperating genetic changes in mice with a retroviral insertional mutagenesis approach. CBFB encodes a transcription factors that associates with other nuclear proteins and regulates expression of target genes. Identification of downstream target genes of CBFB will lead to better understanding of its role in leukemogenesis, and potentially new diagnostic and therapeutic targets. We have used the cDNA microarray technology to analyze gene expression changes in leukemic cells harboring the chromosome 16 inversion and have identified potential target genes. Knowledge of normal hematopoiesis will enhance our understanding of leukemogenic process. To understand the role of Cbfb in hematopoiesis and other developmental processes, mice with a Cbfb-GFP knock-in fusion are being generated. Finally, new therapeutic approaches for AML that specifically counteract the function of CBFB-MYH11 will be tested in our established murine leukemia model.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Human Genome Research Institute (NHGRI)
• Type: Intramural Research (Z01)
• Project #: 1Z01HG000030-07
• Application #: 6556068
• Study Section: (GMBB)
• Support Year: 7
• Fiscal Year: 2001

Institution

• Name: Human Genome Research
• Country: United States

Publications

Han, Wonshik; Nicolau, Monica; Noh, Dong-Young et al. (2010) Characterization of molecular subtypes of Korean breast cancer: an ethnically and clinically distinct population. Int J Oncol 37:51-9

Belele, Christiane L; English, Milton A; Chahal, Jagman et al. (2009) Differential requirement for Gata1 DNA binding and transactivation between primitive and definitive stages of hematopoiesis in zebrafish. Blood 114:5162-72

van de Sluis, Bart; Muller, Patricia; Duran, Karen et al. (2007) Increased activity of hypoxia-inducible factor 1 is associated with early embryonic lethality in Commd1 null mice. Mol Cell Biol 27:4142-56

Zhao, Ling; Cannons, Jennifer L; Anderson, Stacie et al. (2007) CBFB-MYH11 hinders early T-cell development and induces massive cell death in the thymus. Blood 109:3432-40

Markus, Jan; Garin, Matthew T; Bies, Juraj et al. (2007) Methylation-independent silencing of the tumor suppressor INK4b (p15) by CBFbeta-SMMHC in acute myelogenous leukemia with inv(16). Cancer Res 67:992-1000

Carella, C; Bonten, J; Sirma, S et al. (2007) MN1 overexpression is an important step in the development of inv(16) AML. Leukemia 21:1679-90

Lee, Sanggyu; Chen, Jianjun; Zhou, Guolin et al. (2006) Gene expression profiles in acute myeloid leukemia with common translocations using SAGE. Proc Natl Acad Sci U S A 103:1030-5

Kuo, Ya-Huei; Landrette, Sean F; Heilman, Susan A et al. (2006) Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell 9:57-68

Kundu, Mondira; Compton, Sheila; Garrett-Beal, Lisa et al. (2005) Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma. Blood 106:3621-4

van Wijnen, Andre J; Stein, Gary S; Gergen, J Peter et al. (2004) Nomenclature for Runt-related (RUNX) proteins. Oncogene 23:4209-10