Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia
Abstract
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 insigh...Continue Reading
Associated Datasets
References
IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia.
A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia
Citations
Intrinsic disorder controls two functionally distinct dimers of the master transcription factor PU.1
High expression of PU.1 is associated with Her-2 and shorter survival in patients with breast cancer
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