Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1

Frank Rosenbauer, Katharina Wagner, Jeffery L. Kutok, Hiromi Iwasaki, Michelle M. Le Beau, Yutaka Okuno, Koichi Akashi, Steven Fiering, Daniel G. Tenen

Research output: Contribution to journalArticle

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Abstract

Transcription factors are believed to have a dominant role in acute myeloid leukemia (AML). This idea is supported by analysis of gene-knockout mice, which uncovered crucial roles of several transcription factors in normal hematopoiesis, and of individuals with leukemia, in whom transcription factors are frequently downregulated or mutated. However, analysis of knockout animals has not shown a direct link between abrogated transcription factors and the pathogenesis of AML. Sfpi1, encoding the lineage-specific transcription factor PU.1, is indispensable for normal myeloid and lymphoid development. We found that mice carrying hypomorphic Sfpi1 alleles that reduce PU.1 expression to 20% of normal levels, unlike mice carrying homo- or heterozygous deletions of Sfpi1, developed AML. Unlike complete or 50% loss, 80% loss of PU.1 induced a precancerous state characterized by accumulation of an abnormal precursor pool retaining responsiveness to G-CSF with disruption of M- and GM-CSF pathways. Malignant transformation was associated with a high frequency of clonal chromosomal changes. Retroviral restoration of PU.1 expression rescued myeloid differentiation of mutant progenitors and AML blasts. These results suggest that tightly graded reduction, rather than complete loss, of a lineage-indispensable transcription factor can induce AML.

Original languageEnglish
Pages (from-to)624-630
Number of pages7
JournalNature genetics
Volume36
Issue number6
DOIs
Publication statusPublished - Jun 1 2004

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Acute Myeloid Leukemia
Transcription Factors
Gene Knockout Techniques
Hematopoiesis
Granulocyte Colony-Stimulating Factor
Granulocyte-Macrophage Colony-Stimulating Factor
Knockout Mice
proto-oncogene protein Spi-1
Leukemia
Down-Regulation
Alleles

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Rosenbauer, F., Wagner, K., Kutok, J. L., Iwasaki, H., Le Beau, M. M., Okuno, Y., ... Tenen, D. G. (2004). Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nature genetics, 36(6), 624-630. https://doi.org/10.1038/ng1361

Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. / Rosenbauer, Frank; Wagner, Katharina; Kutok, Jeffery L.; Iwasaki, Hiromi; Le Beau, Michelle M.; Okuno, Yutaka; Akashi, Koichi; Fiering, Steven; Tenen, Daniel G.

In: Nature genetics, Vol. 36, No. 6, 01.06.2004, p. 624-630.

Research output: Contribution to journalArticle

Rosenbauer, F, Wagner, K, Kutok, JL, Iwasaki, H, Le Beau, MM, Okuno, Y, Akashi, K, Fiering, S & Tenen, DG 2004, 'Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1', Nature genetics, vol. 36, no. 6, pp. 624-630. https://doi.org/10.1038/ng1361
Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nature genetics. 2004 Jun 1;36(6):624-630. https://doi.org/10.1038/ng1361
Rosenbauer, Frank ; Wagner, Katharina ; Kutok, Jeffery L. ; Iwasaki, Hiromi ; Le Beau, Michelle M. ; Okuno, Yutaka ; Akashi, Koichi ; Fiering, Steven ; Tenen, Daniel G. / Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. In: Nature genetics. 2004 ; Vol. 36, No. 6. pp. 624-630.
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