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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 |
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Main Authors: | , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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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. |
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ISSN: | 0887-6924 1476-5551 |
DOI: | 10.1038/s41375-021-01452-6 |