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A unique role of p53 haploinsufficiency or loss in the development of acute myeloid leukemia with FLT3-ITD mutation

With an incidence of ~50%, the absence or reduced protein level of p53 is much more common than TP53 mutations in acute myeloid leukemia (AML). AML with FLT3 -ITD (internal tandem duplication) mutations has an unfavorable prognosis and is highly associated with wt-p53 dysfunction. While TP53 mutatio...

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Published in:Leukemia 2022-03, Vol.36 (3), p.675-686
Main Authors: Yang, Min, Pan, Zengkai, Huang, Kezhi, Büsche, Guntram, Liu, Hongyun, Göhring, Gudrun, Rumpel, Regina, Dittrich-Breiholz, Oliver, Talbot, Steven, Scherr, Michaela, Chaturvedi, Anuhar, Eder, Matthias, Skokowa, Julia, Zhou, Jianfeng, Welte, Karl, von Neuhoff, Nils, Liu, Ligen, Ganser, Arnold, Li, Zhixiong
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Language:English
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Summary:With an incidence of ~50%, the absence or reduced protein level of p53 is much more common than TP53 mutations in acute myeloid leukemia (AML). AML with FLT3 -ITD (internal tandem duplication) mutations has an unfavorable prognosis and is highly associated with wt-p53 dysfunction. While TP53 mutation in the presence of FLT3-ITD does not induce AML in mice, it is not clear whether p53 haploinsufficiency or loss cooperates with FLT3 -ITD in the induction of AML. Here, we generated FLT3 -ITD knock-in; p53 knockout (heterozygous and homozygous) double-transgenic mice and found that both alterations strongly cooperated in the induction of cytogenetically normal AML without increasing the self-renewal potential. At the molecular level, we found the strong upregulation of Htra3 and the downregulation of Lin28a , leading to enhanced proliferation and the inhibition of apoptosis and differentiation. The co-occurrence of Htra3 overexpression and Lin28a knockdown, in the presence of FLT3-ITD, induced AML with similar morphology as leukemic cells from double-transgenic mice. These leukemic cells were highly sensitive to the proteasome inhibitor carfilzomib. Carfilzomib strongly enhanced the activity of targeting AXL (upstream of FLT3 ) against murine and human leukemic cells. Our results unravel a unique role of p53 haploinsufficiency or loss in the development of FLT3 -ITD + AML.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-021-01452-6