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Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction

Menin/MEN1 is a scaffold protein that participates in proliferation, regulation of gene transcription, DNA damage repair, and signal transduction. In hematological malignancies harboring the KMT2A/MLL1 (MLLr) chromosomal rearrangements, the interaction of the oncogenic fusion protein MLLr with MEN1...

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Autores principales: Wolffhardt, Tatjana Magdalena, Ketzer, Franz, Telese, Stefano, Wirth, Thomas, Ushmorov, Alexey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670986/
https://www.ncbi.nlm.nih.gov/pubmed/38003662
http://dx.doi.org/10.3390/ijms242216472
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author Wolffhardt, Tatjana Magdalena
Ketzer, Franz
Telese, Stefano
Wirth, Thomas
Ushmorov, Alexey
author_facet Wolffhardt, Tatjana Magdalena
Ketzer, Franz
Telese, Stefano
Wirth, Thomas
Ushmorov, Alexey
author_sort Wolffhardt, Tatjana Magdalena
collection PubMed
description Menin/MEN1 is a scaffold protein that participates in proliferation, regulation of gene transcription, DNA damage repair, and signal transduction. In hematological malignancies harboring the KMT2A/MLL1 (MLLr) chromosomal rearrangements, the interaction of the oncogenic fusion protein MLLr with MEN1 has been shown to be essential. MEN1 binders inhibiting the MEN1 and KMT2A interaction have been shown to be effective against MLLr AML and B-ALL in experimental models and clinical studies. We hypothesized that in addition to the MEN1–KMT2A interaction, alternative mechanisms might be instrumental in the MEN1 dependency of leukemia. We first mined and analyzed data from publicly available gene expression databases, finding that the dependency of B-ALL cell lines on MEN1 did not correlate with the presence of MLLr. Using shRNA-mediated knockdown, we found that all tested B-ALL cell lines were sensitive to MEN1 depletion, independent of the underlying driver mutations. Most multiple myeloma cell lines that did not harbor MLLr were also sensitive to the genetic depletion of MEN1. We conclude that the oncogenic role of MEN1 is not limited to the interaction with KMT2A. Our results suggest that targeted degradation of MEN1 or the development of binders that induce global changes in the MEN1 protein structure may be more efficient than the inhibition of individual MEN1 protein interactions.
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spelling pubmed-106709862023-11-17 Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction Wolffhardt, Tatjana Magdalena Ketzer, Franz Telese, Stefano Wirth, Thomas Ushmorov, Alexey Int J Mol Sci Article Menin/MEN1 is a scaffold protein that participates in proliferation, regulation of gene transcription, DNA damage repair, and signal transduction. In hematological malignancies harboring the KMT2A/MLL1 (MLLr) chromosomal rearrangements, the interaction of the oncogenic fusion protein MLLr with MEN1 has been shown to be essential. MEN1 binders inhibiting the MEN1 and KMT2A interaction have been shown to be effective against MLLr AML and B-ALL in experimental models and clinical studies. We hypothesized that in addition to the MEN1–KMT2A interaction, alternative mechanisms might be instrumental in the MEN1 dependency of leukemia. We first mined and analyzed data from publicly available gene expression databases, finding that the dependency of B-ALL cell lines on MEN1 did not correlate with the presence of MLLr. Using shRNA-mediated knockdown, we found that all tested B-ALL cell lines were sensitive to MEN1 depletion, independent of the underlying driver mutations. Most multiple myeloma cell lines that did not harbor MLLr were also sensitive to the genetic depletion of MEN1. We conclude that the oncogenic role of MEN1 is not limited to the interaction with KMT2A. Our results suggest that targeted degradation of MEN1 or the development of binders that induce global changes in the MEN1 protein structure may be more efficient than the inhibition of individual MEN1 protein interactions. MDPI 2023-11-17 /pmc/articles/PMC10670986/ /pubmed/38003662 http://dx.doi.org/10.3390/ijms242216472 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wolffhardt, Tatjana Magdalena
Ketzer, Franz
Telese, Stefano
Wirth, Thomas
Ushmorov, Alexey
Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction
title Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction
title_full Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction
title_fullStr Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction
title_full_unstemmed Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction
title_short Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction
title_sort dependency of b-cell acute lymphoblastic leukemia and multiple myeloma cell lines on men1 extends beyond men1–kmt2a interaction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670986/
https://www.ncbi.nlm.nih.gov/pubmed/38003662
http://dx.doi.org/10.3390/ijms242216472
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