Journal article
An activated receptor tyrosine kinase, TEL/PDGFβR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice
Proceedings of the National Academy of Sciences - PNAS, Vol.100(16), pp.9506-9511
08/05/2003
DOI: 10.1073/pnas.1531730100
PMCID: PMC170948
PMID: 12881486
Abstract
The t(8;21)(q22;q22) translocation, occurring in 40% of patients with acute
myeloid leukemia (AML) of the FAB-M2 subtype (AML with maturation), results in
expression of the
RUNX1-CBF2T1
[
AML1
-
ETO
(
AE
)] fusion oncogene. AML/ETO may contribute to leukemogenesis by
interacting with nuclear corepressor complexes that include histone
deacetylases, which mediate the repression of target genes. However,
expression of
AE
is not sufficient to transform primary hematopoietic
cells or cause disease in animals, suggesting that additional mutations are
required. Activating mutations in receptor tyrosine kinases (RTK) are present
in at least 30% of patients with AML. To test the hypothesis that activating
RTK mutations cooperate with
AE
to cause leukemia, we transplanted
retrovirally transduced murine bone marrow coexpressing
TEL-PDGFRB
and
AE
into lethally irradiated syngeneic mice. These mice (19/19,
100%) developed AML resembling M2-AML that was transplantable in secondary
recipients. In contrast, control mice coexpressing with
TEL-PDGFRB
and a DNA-binding-mutant of
AE
developed a nontransplantable
myeloproliferative disease identical to that induced by
TEL-PDGFRB
alone. We used this unique model of AML to test the efficacy of
pharmacological inhibition of histone deacetylase activity by using
trichostatin A and suberoylanilide hydroxamic acid alone or in combination
with the tyrosine kinase inhibitor, imatinib mesylate. We found that although
imatinib prolonged the survival of treated mice, histone deacetylase
inhibitors provided no additional survival benefit. These data demonstrate
that an activated RTK can cooperate with
AE
to cause AML in mice, and
that this system can be used to evaluate novel therapeutic strategies.
Details
- Title: Subtitle
- An activated receptor tyrosine kinase, TEL/PDGFβR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice
- Creators
- Jay L Grisolano - Departments of Medicine and Genetics, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO 63110Julie O'Neal - Departments of Medicine and Genetics, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO 63110Jennifer Cain - Departments of Medicine and Genetics, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO 63110Michael H Tomasson - Departments of Medicine and Genetics, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO 63110
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.100(16), pp.9506-9511
- DOI
- 10.1073/pnas.1531730100
- PMID
- 12881486
- PMCID
- PMC170948
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 08/05/2003
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094546702771
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