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Aggressive acute myeloid leukemia in PU.1/p53 double-mutant mice


PU.1 downregulation within hematopoietic stem and progenitor cells (HSPCs) is the primary mechanism for the development of acute myeloid leukemia (AML) in mice with homozygous deletion of the upstream regulatory element (URE) of PU.1 gene. p53 is a well-known tumor suppressor that is often mutated in human hematologic malignancies including AML and adds to their aggressiveness; however, its genetic deletion does not cause AML in mouse. Deletion of p53 in the PU.1ure/ure mice (PU.1ure/urep53−/−) results in more aggressive AML with shortened overall survival. PU.1ure/urep53−/− progenitors express significantly lower PU.1 levels. In addition to URE deletion we searched for other mechanisms that in the absence of p53 contribute to decreased PU.1 levels in PU.1ure/urep53−/− mice. We found involvement of Myb and miR-155 in downregulation of PU.1 in aggressive murine AML. Upon inhibition of either Myb or miR-155 in vitro the AML progenitors restore PU.1 levels and lose leukemic cell growth similarly to PU.1 rescue. The MYB/miR-155/PU.1 axis is a target of p53 and is activated early after p53 loss as indicated by transient p53 knockdown. Furthermore, deregulation of both MYB and miR-155 coupled with PU.1 downregulation was observed in human AML, suggesting that MYB/miR-155/PU.1 mechanism may be involved in the pathogenesis of AML and its aggressiveness characterized by p53 mutation.

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Primary support: GACR P305/12/1033 Institutional: UNCE 204021, PRVOUK-P24/LF1/3, SVV-2013-266509, BIOCEV—Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (CZ.1.05/1.1.00/02.0109), from the European Regional Development Fund. Other: PB: GAUK 251135 82210, GACR P301/12/P380; MD: GAUK 251070 45410; VP: GACR 305 13-12449P; PL: Leukemia and Lymphoma Research grant.

Authorship Mouse-AML (PB, EK, MD, US), human-AML (VP, AJ, KV), knockdown (PB), FACS (FS, PB), histology (LS), chromatin immunoprecipitation (PB), experimental design (TS, VP), writing (TS, VP, PB, PL).

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Correspondence to T Stopka.

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Basova, P., Pospisil, V., Savvulidi, F. et al. Aggressive acute myeloid leukemia in PU.1/p53 double-mutant mice. Oncogene 33, 4735–4745 (2014).

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