English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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.

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