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

Nature Medicine
Britta WillUlrich Steidl

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

References

Sep 1, 1995·Nature Genetics·A H ReitmairB Liu
Mar 27, 2001·Nature Reviews. Genetics·S H Orkin
Jul 20, 2002·Blood·Beatrice U MuellerDaniel G Tenen
Dec 2, 2004·Molecular and Cellular Biology·Ritsuko ShimizuMasayuki Yamamoto
May 4, 2005·The Journal of Experimental Medicine·Aleksandar DakicStephen L Nutt
Jan 25, 2006·Proceedings of the National Academy of Sciences of the United States of America·Donald MetcalfStephen Nutt
Feb 4, 2006·Blood·Frederick R AppelbaumStephen H Petersdorf
Jul 25, 2006·Nature·Andrei V KrivtsovScott A Armstrong
Aug 19, 2007·The Journal of Clinical Investigation·Ulrich SteidlDaniel G Tenen
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Nov 6, 2009·Blood·Nicola BonadiesBeatrice U Mueller
Apr 28, 2010·The Journal of Experimental Medicine·Yohei MoritaHiromitsu Nakauchi
Jul 16, 2011·Circulation Research·Benoit PourcetInés Pineda-Torra
Nov 24, 2011·The Journal of Experimental Medicine·Brad DykstraGerald de Haan
Nov 30, 2011·Proceedings of the National Academy of Sciences of the United States of America·Wendy W PangIrving L Weissman
Jul 24, 2012·Cell·John S WelchRichard K Wilson
Aug 31, 2012·Science Translational Medicine·Max JanRavindra Majeti
Feb 20, 2014·Proceedings of the National Academy of Sciences of the United States of America·M Ryan Corces-ZimmermanRavindra Majeti

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Citations

Oct 6, 2015·Nature Chemical Biology·Ujunwa C Okoye-OkaforUlrich Steidl
May 25, 2016·Experimental Hematology·Lacramioara BotezatuCyrus Khandanpour
Sep 7, 2016·Frontiers in Oncology·Hanae SatoKeisuke Ito
Oct 21, 2016·Genesis : the Journal of Genetics and Development·Ming YuKathryn E Hentges
Dec 10, 2016·Experimental Hematology·Eirini TrompoukiTeresa V Bowman
Jul 9, 2016·Cell Stem Cell·Luis A Carvajal, Ulrich Steidl
Nov 23, 2017·Frontiers in Oncology·M Ryan CorcesRavindra Majeti
Oct 31, 2017·The Journal of Clinical Investigation·Iléana Antony-DebréUlrich Steidl
Jul 18, 2018·The Journal of Clinical Investigation·Xiaorong GuYogen Saunthararajah
Oct 14, 2018·Blood·Daniel SchuetzmannFrank Rosenbauer
Jan 8, 2020·Nature Reviews. Cancer·David VetrieMhairi Copland
Jun 3, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wei JianYi Qiu
Jun 22, 2019·Nature Communications·Charles C BellMark A Dawson
Apr 13, 2018·The Journal of Experimental Medicine·Reina NagaseToshio Kitamura
Feb 22, 2017·Journal of Hematology & Oncology·Hubert HacklRotraud Wieser
May 15, 2018·Frontiers in Oncology·John Anto Pulikkan, Lucio Hernán Castilla
Apr 22, 2020·Nature Immunology·Koki UedaUlrich Steidl
Sep 21, 2018·American Society of Clinical Oncology Educational Book·Vamsidhar VelchetiYogen Saunthararajah
Jun 26, 2020·Nature·Justin C WheatUlrich Steidl
Jun 21, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mélanie LambertMarie-Hélène David-Cordonnier
Nov 6, 2018·Cancer Discovery·Jiahao Chen, Ulrich Steidl
Nov 15, 2020·International Journal of Molecular Sciences·Min Young KimYi Qiu
Dec 5, 2020·Blood·Jacob StauberUlrich Steidl
May 28, 2020·Biochemical and Biophysical Research Communications·Eunju ShinJi-Yoon Noh
Aug 30, 2016·Cell Stem Cell·Leslie A CrewsCatriona H M Jamieson
Apr 16, 2021·The Journal of Experimental Medicine·James S ChavezEric M Pietras

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