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PMID: 15044690 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 14 ·2004-04-06 ·Pages 4924-9

Castilla LH, Perrat P, Martinez NJ, Landrette SF, Keys R, Oikemus S, Flanegan J, Heilman S, Garrett L, Dutra A, Anderson S, Pihan GA, Wolff L, Liu PP

Abstract

Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.

MeSH Terms
Acute Disease Animals Artificial Gene Fusion Base Sequence Blotting, Southern Core Binding Factor Alpha 1 Subunit Core Binding Factor beta Subunit DNA Primers DNA-Binding Proteins/genetics Leukemia, Myeloid/genetics Mice Molecular Sequence Data NIH 3T3 Cells Polymerase Chain Reaction Retroviridae/physiology Transcription Factor AP-2 Transcription Factors/genetics
Chemicals
Cbfb protein, mouse Core Binding Factor Alpha 1 Subunit Core Binding Factor beta Subunit DNA Primers DNA-Binding Proteins Runx2 protein, mouse Transcription Factor AP-2 Transcription Factors
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Castilla L H
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA. lucio.castilla@umassmed.edu
Perrat P
Martinez N J
Landrette S F
Keys R
Oikemus S
Flanegan J
Heilman S
Garrett L
Dutra A
Anderson S
Pihan G A
Wolff L
Liu P P
References (44)
44 references, click to expand
  1. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development.
    Cell. 1997 May 30;89(5):765-71 PMID: 9182764
  2. Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta.
    Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12359-63 PMID: 8901586
  3. Leukaemia disease genes: large-scale cloning and pathway predictions.
    Nat Genet. 1999 Nov;23(3):348-53 PMID: 10610183
  4. A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc.
    Oncogene. 1999 Nov 25;18(50):7124-34 PMID: 10597314
  5. PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II.
    Cancer Res. 2000 Jan 1;60(1):106-13 PMID: 10646861
  6. A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice.
    Blood. 2000 Sep 1;96(5):1906-13 PMID: 10961893
  7. PLAG1 fusion oncogenes in lipoblastoma.
    Cancer Res. 2000 Sep 1;60(17):4869-72 PMID: 10987300
  8. Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging.
    Oncogene. 2001 Jan 18;20(3):295-302 PMID: 11313958
  9. SHIP1, an SH2 domain containing polyinositol-5-phosphatase, regulates migration through two critical tyrosine residues and forms a novel signaling complex with DOK1 and CRKL.
    J Biol Chem. 2001 Jan 26;276(4):2451-8 PMID: 11031258
  10. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations.
    Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10398-403 PMID: 11526243
  11. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11.
    Cell. 1996 Nov 15;87(4):687-96 PMID: 8929537
  12. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo.
    Cell. 1996 Nov 15;87(4):697-708 PMID: 8929538
  13. Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations.
    Nat Genet. 1997 Feb;15(2):170-4 PMID: 9020842
  14. 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.
    Proc Natl Acad Sci U S A. 1997 May 27;94(11):5697-702 PMID: 9159135
  15. Core binding factor cannot synergistically activate the myeloperoxidase proximal enhancer in immature myeloid cells without c-Myb.
    Mol Cell Biol. 1997 Sep;17(9):5127-35 PMID: 9271390
  16. Oncogenic transcription factors in the human acute leukemias.
    Science. 1997 Nov 7;278(5340):1059-64 PMID: 9353180
  17. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia.
    Nat Genet. 1999 Oct;23(2):144-6 PMID: 10508507
  18. In vivo analysis of the molecular genetics of acute promyelocytic leukemia.
    Oncogene. 2001 Sep 10;20(40):5726-35 PMID: 11607822
  19. T cell regulation of p62(dok) (Dok1) association with Crk-L.
    J Biol Chem. 2001 Dec 7;276(49):45654-61 PMID: 11553620
  20. The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities.
    Cancer Res. 2002 Mar 1;62(5):1510-7 PMID: 11888928
  21. Linkage on chromosome 10 of several murine retroviral integration loci associated with leukaemia.
    J Gen Virol. 2002 Apr;83(Pt 4):819-27 PMID: 11907331
  22. Rearrangement involving chromosomes 1 and 8 in a retroperitoneal lipoma.
    Cancer Genet Cytogenet. 2002 Mar;133(2):156-9 PMID: 11943344
  23. A zinc-finger protein, PLAGL2, induces the expression of a proapoptotic protein Nip3, leading to cellular apoptosis.
    J Biol Chem. 2002 May 3;277(18):15851-8 PMID: 11832486
  24. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia.
    Cancer Cell. 2002 Feb;1(1):63-74 PMID: 12086889
  25. Identification of oncogenes collaborating with p27Kip1 loss by insertional mutagenesis and high-throughput insertion site analysis.
    Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11293-8 PMID: 12151601
  26. Role of Dok1 in cell signaling mediated by RET tyrosine kinase.
    J Biol Chem. 2002 Sep 6;277(36):32781-90 PMID: 12087092
  27. New genes involved in cancer identified by retroviral tagging.
    Nat Genet. 2002 Sep;32(1):166-74 PMID: 12185365
  28. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer.
    Nat Genet. 2002 Sep;32(1):153-9 PMID: 12185366
  29. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice.
    Nat Genet. 2002 Sep;32(1):160-5 PMID: 12185367
  30. Large-scale identification of novel potential disease loci in mouse leukemia applying an improved strategy for cloning common virus integration sites.
    Oncogene. 2002 Oct 17;21(47):7247-55 PMID: 12370816
  31. Long-range effects of retroviral insertion on c-myb: overexpression may be obscured by silencing during tumor growth in vitro.
    J Virol. 2003 Jan;77(2):1059-68 PMID: 12502821
  32. Genomes of murine leukemia viruses isolated from wild mice.
    J Virol. 1981 Sep;39(3):777-91 PMID: 6270351
  33. Normal DBA/2 mouse cells synthesize a glycoprotein which interferes with MCF virus infection.
    Virology. 1982 Nov;123(1):139-51 PMID: 6959413
  34. Contribution of the gag and pol sequences to the leukemogenicity of Friend murine leukemia virus.
    J Virol. 1985 Jun;54(3):864-8 PMID: 3999195
  35. Acute myeloid leukemia induction by amphotropic murine retrovirus (4070A): clonal integrations involve c-myb in some but not all leukemias.
    J Virol. 1991 Jul;65(7):3607-16 PMID: 1645785
  36. Phenotypes of murine leukemia virus-induced tumors: influence of 3' viral coding sequences.
    J Virol. 1992 Oct;66(10):6107-16 PMID: 1326661
  37. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene.
    Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6859-63 PMID: 8341710
  38. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia.
    Science. 1993 Aug 20;261(5124):1041-4 PMID: 8351518
  39. Regulation of the T-cell receptor delta enhancer by functional cooperation between c-Myb and core-binding factors.
    Mol Cell Biol. 1994 Jan;14(1):473-83 PMID: 8264615
  40. Expression of the Runt domain-encoding PEBP2 alpha genes in T cells during thymic development.
    Mol Cell Biol. 1995 Mar;15(3):1662-70 PMID: 7862157
  41. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.
    Cell. 1996 Jan 26;84(2):321-30 PMID: 8565077
  42. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3444-9 PMID: 8622955
  43. Retroviral insertional mutagenesis as a strategy to identify cancer genes.
    Biochim Biophys Acta. 1996 May 16;1287(1):29-57 PMID: 8639705
  44. Proviral insertions induce the expression of bone-specific isoforms of PEBP2alphaA (CBFA1): evidence for a new myc collaborating oncogene.
    Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8646-51 PMID: 9238031
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0400930101
Email
lucio.castilla@umassmed.edu
Published
2004-04-06
Epub
2004-00-24
Pages
4924-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC387350
Subset
IM
Grants
NCI NIH HHS · R01 CA096983 · United States
NCI NIH HHS · R01-CA096983 · United States
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External Links
PubMed source DOI: 10.1073/pnas.0400930101 PMC Full Text View journal details
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