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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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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Author notes

    • Britta Will
    •  & Thomas O Vogler

    These authors contributed equally to this work.


  1. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, USA.

    • Britta Will
    • , Thomas O Vogler
    • , Swathi Narayanagari
    • , Boris Bartholdy
    • , Tihomira I Todorova
    • , Mariana da Silva Ferreira
    • , Jiahao Chen
    • , Jillian Mayer
    • , Laura Barreyro
    • , Luis Carvajal
    • , Daniela Ben Neriah
    • , Michael Roth
    • , Johanna van Oers
    • , Sonja Schaetzlein
    • , Winfried Edelmann
    •  & Ulrich Steidl
  2. Department of Medicine (Oncology), Division of Hemato-Oncology, Albert Einstein College of Medicine–Montefiore Medical Center, Bronx, USA.

    • Yiting Yu
    • , Amit Verma
    •  & Ulrich Steidl
  3. Department of Pathology, Albert Einstein College of Medicine, Bronx, USA.

    • Christine McMahon
  4. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, USA.

    • Winfried Edelmann
    • , Amit Verma
    •  & Ulrich Steidl
  5. Department of Genetics, Albert Einstein College of Medicine, Bronx, USA.

    • Winfried Edelmann
  6. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, USA.

    • Amit Verma
  7. Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, USA.

    • Amit Verma
    •  & Ulrich Steidl


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Britta Will or Ulrich Steidl.

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