TY - JOUR
T1 - Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1
AU - Rosenbauer, Frank
AU - Wagner, Katharina
AU - Kutok, Jeffery L.
AU - Iwasaki, Hiromi
AU - Le Beau, Michelle M.
AU - Okuno, Yutaka
AU - Akashi, Koichi
AU - Fiering, Steven
AU - Tenen, Daniel G.
N1 - Funding Information:
We thank K. Geary, J. Fields, S. Warner and the Dartmouth Transgenic Facility for assistance in generating and keeping the described mice; R. Cruz and A. Radhakrishnan for technical assistance with the SKY analysis; V. Petkova and T. Dayaram for help with the real-time PCRs; S. Dymecki and G. Martin (pK11-FRT-PGKneo-FRT), K.P. Knobeloch (pPNT-loxPneo) and H. Singh (MIG and MIG-PU.1) for constructs and advice; and J.D. Griffin, D.G. Gilliland, A.T. Look and S. Koschmieder for comments on the manuscript. This work was supported by DFG (German research foundation) research fellowships to F.R. and K.W. and by National Institutes of Health grants to M.M.L. and D.G.T.
PY - 2004/6
Y1 - 2004/6
N2 - 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.
AB - 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.
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U2 - 10.1038/ng1361
DO - 10.1038/ng1361
M3 - Article
C2 - 15146183
AN - SCOPUS:2642519463
VL - 36
SP - 624
EP - 630
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 6
ER -