Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia

Britta Will, Thomas O. Vogler, Swathi-Rao Narayanagari, Boris A. Bartholdy, Tihomira I. Todorova, Mariana Da Silva Ferreira, Jiahao Chen, Yiting Yu, Jillian Mayer, Laura Barreyro, Luis Carvajal, Daniela Ben Neriah, Michael Roth, Johanna Van Oers, Sonja Schaetzlein, Christine McMahon, Winfried Edelmann, Amit K. Verma, Ulrich G. Steidl

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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.

Original languageEnglish (US)
Pages (from-to)1172-1181
Number of pages10
JournalNature Medicine
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2015

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Stem cells
Acute Myeloid Leukemia
Transcription Factors
DNA
Stem Cells
Repair
Aging of materials
DNA Mismatch Repair
Cell Aging
Myelodysplastic Syndromes
Epigenomics
Neoplasms
Leukemia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. / Will, Britta; Vogler, Thomas O.; Narayanagari, Swathi-Rao; Bartholdy, Boris A.; Todorova, Tihomira I.; Da Silva Ferreira, Mariana; Chen, Jiahao; Yu, Yiting; Mayer, Jillian; Barreyro, Laura; Carvajal, Luis; Neriah, Daniela Ben; Roth, Michael; Van Oers, Johanna; Schaetzlein, Sonja; McMahon, Christine; Edelmann, Winfried; Verma, Amit K.; Steidl, Ulrich G.

In: Nature Medicine, Vol. 21, No. 10, 01.10.2015, p. 1172-1181.

Research output: Contribution to journalArticle

Will, B, Vogler, TO, Narayanagari, S-R, Bartholdy, BA, Todorova, TI, Da Silva Ferreira, M, Chen, J, Yu, Y, Mayer, J, Barreyro, L, Carvajal, L, Neriah, DB, Roth, M, Van Oers, J, Schaetzlein, S, McMahon, C, Edelmann, W, Verma, AK & Steidl, UG 2015, 'Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia', Nature Medicine, vol. 21, no. 10, pp. 1172-1181. https://doi.org/10.1038/nm.3936
Will, Britta ; Vogler, Thomas O. ; Narayanagari, Swathi-Rao ; Bartholdy, Boris A. ; Todorova, Tihomira I. ; Da Silva Ferreira, Mariana ; Chen, Jiahao ; Yu, Yiting ; Mayer, Jillian ; Barreyro, Laura ; Carvajal, Luis ; Neriah, Daniela Ben ; Roth, Michael ; Van Oers, Johanna ; Schaetzlein, Sonja ; McMahon, Christine ; Edelmann, Winfried ; Verma, Amit K. ; Steidl, Ulrich G. / Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. In: Nature Medicine. 2015 ; Vol. 21, No. 10. pp. 1172-1181.
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