Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins.

Halilovic, Melisa, Abdelsalam, Mohamed, Zabkiewicz, Joanna ORCID: https://orcid.org/0000-0003-0951-3825, Lazenby, Michelle, Alvares, Caroline ORCID: https://orcid.org/0000-0003-4391-9802, Schmidt, Matthias, Brenner, Walburgis, Najafi, Sara, Oehme, Ina, Hieber, Christoph, Zeyn, Yanira, Bros, Matthias, Sippl, Wolfgang and Krämer, Oliver H 2024. Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins. Leukemia 10.1038/s41375-024-02405-5

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Abstract

Internal tandem duplications in the FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (p < 0.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a Danio rerio model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (p < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (p < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit. [Abstract copyright: © 2024. The Author(s).]

Item Type:	Article
Status:	In Press
Schools:	Medicine
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0887-6924
Date of First Compliant Deposit:	10 October 2024
Date of Acceptance:	2 September 2024
Last Modified:	10 Oct 2024 08:43
URI:	https://orca.cardiff.ac.uk/id/eprint/172782

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