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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 insight into the formation and progression of preleukemic stem cells in AML.

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Figure 1: Minimal reduction of PU.1 expression is sufficient to trigger AML development in mice.
Figure 2: Characterization of UREhetMsh2−/−-induced AML.
Figure 3: Role of Irf8 downregulation in compound mutant AML cells.
Figure 4: Minimal PU.1 expression reduction induces a preleukemic state.
Figure 5: Similarities between mouse UREhetMsh2−/− and human myeloid leukemogenesis.

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Gene Expression Omnibus

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Acknowledgements

We would like to thank K. Ozato for kindly providing the Irf8 expression vector. We thank A. Skoultchi, K. Gritsman and members of the Steidl laboratory for very helpful discussions and suggestions. We also thank G. Simkin and D. Sun of the Einstein Stem Cell Isolation and Xenotransplantation Facility (funded through New York Stem Cell Science (NYSTEM) grant no. C029154), C. Montagna and Z.X. Yang from the Einstein Genome Imaging Facility, D. Reynolds and W. Tran from the Einstein Genomics Core Facility and P. Schultes from the Einstein Department of Cell Biology for expert technical assistance. This work was supported by US National Institutes of Health (NIH) grant R00CA131503 (U.S.), Albert Einstein Cancer Center Core Support grant P30CA013330 and The Gabrielle's Angel Foundation for Cancer Research (U.S.). U.S. is a Research Scholar of the Leukemia and Lymphoma Society and the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine.

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B.W., U.S., A.V. and W.E. designed the study and experiments. B.W., T.O.V., S.N., T.I.T., J.M., M.d.S.F., L.C., D.B.N., M.R., J.v.O. and S.S. conducted experiments. B.B., J.C., Y.Y., L.B. and B.W. performed gene expression, large data set and pathway analyses. C.M. and A.V. performed cell pathological analyses. B.W., T.O.V. and U.S. wrote the manuscript.

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Correspondence to Britta Will or Ulrich Steidl.

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Will, B., Vogler, T., Narayanagari, S. et al. Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. Nat Med 21, 1172–1181 (2015). https://doi.org/10.1038/nm.3936

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