Year-end Sale % OFF 
Abstract
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.
Highlights
INTRODUCTION Mutations in theTP53 gene are very common in solid tumor with an incidence of up to 90% in certain cancers [1, 2]
Our study presents a powerful synergy between FLT3-internal tandem duplication (ITD) and p53 haploinsufficiency or loss in the induction of acute myeloid leukemia (AML) and emphasizes more careful analysis of p53 deregulation in AML
The biallelic loss of TP53 is a rare event in AML, the TP53 tumor suppressor gene is frequently inactivated in tumors through a two-hit mechanism, in which one allele carries a missense mutation and the other allele is lost by the deletion of human chromosome 17p, which may give rise to the complete loss of wt-p53 function
Summary
INTRODUCTION Mutations in theTP53 gene are very common in solid tumor with an incidence of up to 90% in certain cancers [1, 2]. With an incidence of ~50%, absent/reduced protein level of p53 is much more common than TP53 mutations in AML [3, 7,8,9]. Functional nuclear p53 protein has been shown to be strongly reduced in AML patients (up to 98% in patients with FLT3-ITD and NPM1mut) [10]. AML with FLT3-ITD mutations is highly associated with wtp dysfunction via additional different ways such as MDM2/MDM4 overexpression [11] (Supplementary Fig. 1), SIRT1 overexpression (resulting p53 deacetylation), PI3K/AKT pathway activation (promoting MDM2-mediated p53 degradation), STAT/MAPK pathway activation with BCL2 accumulation (opposing p53 activity), disturbing the nucleocytoplasmic shuttling of p53 [10], dysregulation of NPM (in patients with FLT3-ITD and NPM1 mutant) [12], and aberrant expression of certain miRNAs (e.g., miR-125b) [13].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
