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Science 20 August 1993:
Vol. 261. no. 5124, pp. 1041 - 1044
DOI: 10.1126/science.8351518
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Articles

Science, Vol 261, Issue 5124, 1041-1044
Copyright © 1993 by American Association for the Advancement of Science

articles

Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia

P Liu, SA Tarle, A Hajra, DF Claxton, P Marlton, M Freedman, MJ Siciliano, and FS Collins

Howard Hughes Medical Institute, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109.

The pericentric inversion of chromosome 16 [inv(16)(p13q22)] is a characteristic karyotypic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. The 16p and 16q breakpoints were pinpointed by yeast artificial chromosome and cosmid cloning, and the two genes involved in this inversion were identified. On 16q the inversion occurred near the end of the coding region for CBF beta, also known as PEBP2 beta, a subunit of a heterodimeric transcription factor regulating genes expressed in T cells; on 16p a smooth muscle myosin heavy chain (SMMHC) gene (MYH11) was interrupted. In six of six inv(16) patient samples tested, an in-frame fusion messenger RNA was demonstrated that connected the first 165 amino acids of CBF beta with the tail region of SMMHC. The repeated coiled coil of SMMHC may result in dimerization of the CBF beta fusion protein, which in turn would lead to alterations in transcriptional regulation and contribute to leukemic transformation.


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Development 128, 2639-2648
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T. Blake, N. Adya, C.-H. Kim, A. C. Oates, L. Zon, A. Chitnis, B. M. Weinstein, and P. P. Liu (2000)
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Blood 96, 3154-3160
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K. L. Rhoades, C. J. Hetherington, N. Harakawa, D. A. Yergeau, L. Zhou, L.-Q. Liu, M.-T. Little, D. G. Tenen, and D.-E. Zhang (2000)
Blood 96, 2108-2115
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Blood 95, 3514-3519
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D. K. Strom, J. Nip, J. J. Westendorf, B. Linggi, B. Lutterbach, J. R. Downing, N. Lenny, and S. W. Hiebert (2000)
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B. Lutterbach, J. J. Westendorf, B. Linggi, S. Isaac, E. Seto, and S. W. Hiebert (2000)
J. Biol. Chem. 275, 651-656
   Abstract »    Full Text »    PDF »
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T.-L. Gu, T. L. Goetz, B. J. Graves, and N. A. Speck (2000)
Mol. Cell. Biol. 20, 91-103
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R. Fenrick, J. M. Amann, B. Lutterbach, L. Wang, J. J. Westendorf, J. R. Downing, and S. W. Hiebert (1999)
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B. Lowenberg, J. R. Downing, and A. Burnett (1999)
N. Engl. J. Med. 341, 1051-1062
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A. F. Lewis, T. Stacy, W. R. Green, L. Taddesse-Heath, J. W. Hartley, and N. A. Speck (1999)
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M. Osato, N. Asou, E. Abdalla, K. Hoshino, H. Yamasaki, T. Okubo, H. Suzushima, K. Takatsuki, T. Kanno, K. Shigesada, et al. (1999)
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L. Li and J. Gergen (1999)
Development 126, 3313-3322
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The Leukemic Protein Core Binding Factor beta  (CBFbeta )-Smooth-Muscle Myosin Heavy Chain Sequesters CBFalpha 2 into Cytoskeletal Filaments and Aggregates.
N. Adya, T. Stacy, N. A. Speck, and P. P. Liu (1998)
Mol. Cell. Biol. 18, 7432-7443
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CBFbeta -SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-Damaging Agents.
M. Britos-Bray, M. Ramirez, W. Cao, X. Wang, P. P. Liu, C. I. Civin, and A. D. Friedman (1998)
Blood 92, 4344-4352
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In Vivo Footprinting of the Enhancer Sequences in the Upstream Long Terminal Repeat of Moloney Murine Leukemia Virus: Differential Binding of Nuclear Factors in Different Cell Types.
S. W. Granger and H. Fan (1998)
J. Virol. 72, 8961-8970
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CBFA2(AML1) Translocations With Novel Partner Chromosomes in Myeloid Leukemias: Association With Prior Therapy.
D. Roulston, R. Espinosa III, G. Nucifora, R. A. Larson, M. M. Le Beau, and J. D. Rowley (1998)
Blood 92, 2879-2885
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S. C. Kogan, E. Lagasse, S. Atwater, S.-c. Bae, I. Weissman, Y. Ito, and J. M. Bishop (1998)
PNAS 95, 11863-11868
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Distinct C/EBP functions are required for eosinophil lineage commitment and maturation.
C. Nerlov, K. M. McNagny, G. Döderlein, E. Kowenz-Leutz, and T. Graf (1998)
Genes & Dev. 12, 2413-2423
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Multiplex Reverse Transcription-Polymerase Chain Reaction for Simultaneous Screening of 29 Translocations and Chromosomal Aberrations in Acute Leukemia.
N. Pallisgaard, P. Hokland, D. C. Riishoj, B. Pedersen, and P. Jorgensen (1998)
Blood 92, 574-588
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Multiple Functional Domains of AML1: PU.1 and C/EBPalpha Synergize with Different Regions of AML1.
M. S. Petrovick, S. W. Hiebert, A. D. Friedman, C. J. Hetherington, D. G. Tenen, and D.-E. Zhang (1998)
Mol. Cell. Biol. 18, 3915-3925
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Cytoplasmic Sequestration of the Polyomavirus Enhancer Binding Protein 2 (PEBP2)/Core Binding Factor alpha  (CBFalpha ) Subunit by the Leukemia-Related PEBP2/CBFbeta -SMMHC Fusion Protein Inhibits PEBP2/CBF-Mediated Transactivation.
Y. Kanno, T. Kanno, C. Sakakura, S.-C. Bae, and Y. Ito (1998)
Mol. Cell. Biol. 18, 4252-4261
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B. Lutterbach, D. Sun, J. Schuetz, and S. W. Hiebert (1998)
Mol. Cell. Biol. 18, 3604-3611
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M. E. Rothenberg (1998)
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Intrinsic Transcriptional Activation-Inhibition Domains of the Polyomavirus Enhancer Binding Protein 2/Core Binding Factor alpha  Subunit Revealed in the Presence of the beta  Subunit.
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   Abstract »    Full Text »    PDF »
Characterization and Use of an Antibody Detecting the CBFbeta -SMMHC Fusion Protein in inv(16)/t(16;16)-Associated Acute Myeloid Leukemias.
D. S. Viswanatha, I.-M. Chen, P. P. Liu, M. L. Slovak, C. Rankin, D. R. Head, and C. L. Willman (1998)
Blood 91, 1882-1890
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The AML1/ETO(MTG8) and AML1/Evi-1 Leukemia-Associated Chimeric Oncoproteins Accumulate PEBP2beta (CBFbeta ) in the Nucleus More Efficiently Than Wild-Type AML1.
K. Tanaka, T. Tanaka, M. Kurokawa, Y. Imai, S. Ogawa, K. Mitani, Y. Yazaki, and H. Hirai (1998)
Blood 91, 1688-1699
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The AML1-MTG8 Leukemic Fusion Protein Forms a Complex with a Novel Member of the MTG8(ETO/CDR) Family, MTGR1.
I. Kitabayashi, K. Ida, F. Morohoshi, A. Yokoyama, N. Mitsuhashi, K. Shimizu, N. Nomura, Y. Hayashi, and M. Ohki (1998)
Mol. Cell. Biol. 18, 846-858
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Overexpression, Purification, and Biophysical Characterization of the Heterodimerization Domain of the Core-binding Factor beta  Subunit.
X. Huang, B. E. Crute, C. Sun, Y.-Y. Tang, J. J. Kelley III, A. F. Lewis, K. L. Hartman, T. M. Laue, N. A. Speck, and J. H. Bushweller (1998)
J. Biol. Chem. 273, 2480-2487
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A Xenopus homologue of aml-1 reveals unexpected patterning mechanisms leading to the formation of embryonic blood.
W. Tracey, M. Pepling, M. Horb, G. Thomsen, and J. Gergen (1998)
Development 125, 1371-1380
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The t(8;21) Fusion Product, AML-1-ETO, Associates with C/EBP-alpha , Inhibits C/EBP-alpha -Dependent Transcription, and Blocks Granulocytic Differentiation.
J. J. Westendorf, C. M. Yamamoto, N. Lenny, J. R. Downing, M. E. Selsted, and S. W. Hiebert (1998)
Mol. Cell. Biol. 18, 322-333
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Fifty Years of Studies of the Biology and Therapy of Childhood Leukemia.
J. H. Kersey (1997)
Blood 90, 4243-4251
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Transcription Factors, Normal Myeloid Development, and Leukemia.
D. G. Tenen, R. Hromas, J. D. Licht, and D.-E. Zhang (1997)
Blood 90, 489-519
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Redox Regulation of the DNA Binding Activity in Transcription Factor PEBP2. THE ROLES OF TWO CONSERVED CYSTEINE RESIDUES.
Y. Akamatsu, T. Ohno, K. Hirota, H. Kagoshima, J. Yodoi, and K. Shigesada (1997)
J. Biol. Chem. 272, 14497-14500
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Hematopoiesis in the fetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor.
M. Niki, H. Okada, H. Takano, J. Kuno, K. Tani, H. Hibino, S. Asano, Y. Ito, M. Satake, and T. Noda (1997)
PNAS 94, 5697-5702
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Distinct roles for P-CREB and LEF-1 in TCR alpha enhancer assembly and activation on chromatin templates in vitro..
T P Mayall, P L Sheridan, M R Montminy, and K A Jones (1997)
Genes & Dev. 11, 887-899
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Functional Dissection of the alpha and beta Subunits of Transcription Factor PEBP2 and the Redox Susceptibility of Its DNA Binding Activity.
H. Kagoshima, Y. Akamatsu, Y. Ito, and K. Shigesada (1996)
J. Biol. Chem. 271, 33074-33082