Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia.
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.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Britta
B
Will
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Thomas O
TO
Vogler
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Swathi
S
Narayanagari
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Boris
B
Bartholdy
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Tihomira I
TI
Todorova
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Mariana
M
da Silva Ferreira
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Jiahao
J
Chen
Department of Medicine (Oncology), Division of Hemato-Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, USA.
Yiting
Y
Yu
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Jillian
J
Mayer
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Laura
L
Barreyro
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Luis
L
Carvajal
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Daniela Ben
DB
Neriah
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Michael
M
Roth
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Johanna
J
van Oers
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.
Sonja
S
Schaetzlein
Department of Pathology, Albert Einstein College of Medicine, Bronx, USA.
Christine
C
McMahon
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, USA.|Department of Genetics, Albert Einstein College of Medicine, Bronx, USA.
Winfried
W
Edelmann
Department of Medicine (Oncology), Division of Hemato-Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, USA.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, USA.|Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, USA.|Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, USA.
Amit
A
Verma
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.|Department of Medicine (Oncology), Division of Hemato-Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, USA.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, USA.|Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, USA.
Ulrich
U
Steidl
D000818:Animals; D018450:Disease Progression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011289:Preleukemia / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1