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NPM1C, une cible dans le traitement des leucémies aigues myéloides

Abstract : Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Despite improvements in understanding the biology of AML, survival rates remain quite low. Prognosis of AML patients largely depends on acquired cytogenetic and molecular abnormalities. Nucleophosmin-1 (NPM1) is an essential gene encoding for a nucleocytoplasmic shuttling protein mainly localized to the nucleolus. Among several functions, NPM1 plays major roles in stabilization of the p14ARF tumor suppressor protein, regulation of ribosome biogenesis, control of centrosome duplication, response to stress stimuli and P53 activation. NPM1 is one of the most frequently mutated genes in AML accounting for around one third of patients (NPM1c AML). In mutant NPM1c proteins, critical tryptophan residues in the C-terminus are lost and a de novo nuclear export signal is created. This leads to ectopic and aberrant accumulation of NPM1c, along with normal NPM1, in the cytoplasm of AML blasts, thus playing a major role in leukemogenesis. The promyelocytic leukemia protein (PML) tumor suppressor organizes nuclear bodies (NB) domains that control proteolysis and P53-driven senescence. PML NBs are disorganized in NPM1c AML. Retinoic acid (RA), a hormone favoring differentiation of myeloid cells, increases survival of chemotherapy-treated NPM1c AMLs. We and others previously reported that RA and Arsenic trioxide (ATO) synergize to induce NPM1c degradation and to inhibit growth and induce apoptosis of NPM1c cells. Importantly, combined RA/ATO treatment significantly reduced bone marrow blasts in some NPM1c AML patients and restored the subnuclear localization of both NPM1 and PML. The main objective of the current work was to unravel the biochemical pathways driving NPM1c catabolism and to elucidate the molecular mechanisms of RA/ATO anti-leukemic activities. We demonstrate that PML is required for RA/ATO-induced NPM1c degradation. In primary NPM1c-AML blasts, RA rapidly upregulates the initial low basal PML expression through Pin-1 inhibition prior to NPM1c clearance. This RA-induced PML stabilizes P53 and primes blasts for ATO-driven nuclear body reformation, yielding hyper-activation of P53. RA/ATO combination elicits PML-dependent responses, associated with in vivo P53 activation in NPM1c AML xenografts. Importantly, RA/ATO-initiated a transient complete remission in a NPM1c-AML patient demonstrating clinical relevance of this combination. We also demonstrate that ATO-driven NPM1c degradation happens via the PML/SUMO/RNF4/Proteasome pathway, which cooperates with direct RA-induced ubiquitination. By establishing the mechanisms underlying RA and ATO sensitivity of NPM1c AMLs, our studies identify a striking parallelism with APL, paving the way to the crafting of curative targeted therapies in this category of AML patients.
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https://tel.archives-ouvertes.fr/tel-03036805
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Submitted on : Wednesday, December 2, 2020 - 6:53:07 PM
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Rita Hleihel. NPM1C, une cible dans le traitement des leucémies aigues myéloides. Médecine humaine et pathologie. Université Sorbonne Paris Cité, 2019. Français. ⟨NNT : 2019USPCC095⟩. ⟨tel-03036805⟩

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