Molecular Pathogenesis of Chromosome 16 Inversion in Human Leukemia

Liu, P P.

Abstract

A pericentric chromosome 16 inversion is present in almost 100% of patients with M4Eo subtype of acute myeloid leukemia. It is also detected in other types of leukemia as well at a lower frequency. A fusion gene between CBFB, the gene for a subunit of transcription factor CBF/PEBP2 on 16q22, and MYH11, which codes for smooth muscle myosin heavy chain, is generated by this chromosome 16 inversion. We have shown that the CBFB-MYH11 fusion gene can transform NIH 3T3 cells and this transformation requires the CBFB domain for binding with its partner CBFa and the MYH11 domain for multimerization. We also found that this transformation correlates with altered transactivation of potential target genes of CBF/PEBP2 and a unique subcellular localization pattern of the fusion protein. Further analysis of the CBFB-MYH11 fusion gene and its produced protein is in progress, including further dissecting the functional domains of the protein, identification of potential interactions of the protein with other transcription factors, identification of target genes involved in the transformation, and the potential interaction with other oncogenes and/or tumor suppressor genes. A mouse model of the human leukemia is being generated through several strategies, including inserting the fusion cDNA under the control of several different promoters, and recreating the inversion by homologous recombination.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Human Genome Research Institute (NHGRI)
• Type: Intramural Research (Z01)
• Project #: 1Z01HG000030-01
• Application #: 5203420
• Support Year: 1
• Fiscal Year: 1995

Institution

• Name: National Human Genome Research Institute
• 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

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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

Castilla, L H; Perrat, P; Martinez, N J et al. (2004) Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Proc Natl Acad Sci U S A 101:4924-9