TY - JOUR
T1 - Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia
AU - Will, Britta
AU - Vogler, Thomas O.
AU - Narayanagari, Swathi
AU - Bartholdy, Boris
AU - Todorova, Tihomira I.
AU - Da Silva Ferreira, Mariana
AU - Chen, Jiahao
AU - Yu, Yiting
AU - Mayer, Jillian
AU - Barreyro, Laura
AU - Carvajal, Luis
AU - Neriah, Daniela Ben
AU - Roth, Michael
AU - Van Oers, Johanna
AU - Schaetzlein, Sonja
AU - McMahon, Christine
AU - Edelmann, Winfried
AU - Verma, Amit
AU - Steidl, Ulrich
N1 - Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet, moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reductions in PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in a 35% reduction of PU.1 expression, was sufficient to induce myeloid-biased preleukemic stem cells and their subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1-cooperating transcription factor, Irf8. Notably, we found marked molecular similarities between the disease in these mice and human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor, which commonly occurs in human disease, is sufficient to initiate cancer development, and it provides mechanistic insight into the formation and progression of preleukemic stem cells in AML.
AB - Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet, moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reductions in PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging. Heterozygous deletion of an enhancer of PU.1, which resulted in a 35% reduction of PU.1 expression, was sufficient to induce myeloid-biased preleukemic stem cells and their subsequent transformation to AML in a DNA mismatch repair-deficient background. AML progression was mediated by inhibition of expression of a PU.1-cooperating transcription factor, Irf8. Notably, we found marked molecular similarities between the disease in these mice and human myelodysplastic syndrome and AML. This study demonstrates that minimal reduction of a key lineage-specific transcription factor, which commonly occurs in human disease, is sufficient to initiate cancer development, and it provides mechanistic insight into the formation and progression of preleukemic stem cells in AML.
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U2 - 10.1038/nm.3936
DO - 10.1038/nm.3936
M3 - Article
C2 - 26343801
AN - SCOPUS:84943665619
SN - 1078-8956
VL - 21
SP - 1172
EP - 1181
JO - Nature Medicine
JF - Nature Medicine
IS - 10
ER -