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A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma

There is increasing evidence that the T-cell protein, Lck, is involved in the pathogenesis of chronic lymphocytic leukemia (CLL) as well as other leukemias and lymphomas. We previously discovered that Lck binds to domain 5 of inositol 1,4,5-trisphosphate receptors (IP3R) to regulate Ca2+ homeostasis...

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Autores principales: Harr, Michael, Lavik, Andrew, McColl, Karen, Zhong, Fei, Haberer, Ben, Aldabbagh, Khadijah, Yee, Vivien, Distelhorst, Clark W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882657/
https://www.ncbi.nlm.nih.gov/pubmed/36711753
http://dx.doi.org/10.21203/rs.3.rs-2436910/v1
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author Harr, Michael
Lavik, Andrew
McColl, Karen
Zhong, Fei
Haberer, Ben
Aldabbagh, Khadijah
Yee, Vivien
Distelhorst, Clark W.
author_facet Harr, Michael
Lavik, Andrew
McColl, Karen
Zhong, Fei
Haberer, Ben
Aldabbagh, Khadijah
Yee, Vivien
Distelhorst, Clark W.
author_sort Harr, Michael
collection PubMed
description There is increasing evidence that the T-cell protein, Lck, is involved in the pathogenesis of chronic lymphocytic leukemia (CLL) as well as other leukemias and lymphomas. We previously discovered that Lck binds to domain 5 of inositol 1,4,5-trisphosphate receptors (IP3R) to regulate Ca2+ homeostasis. Using bioinformatics, we targeted a region within domain 5 of IP3R-1 predicted to facilitate protein-protein interactions (PPIs). We generated a synthetic 21 amino acid peptide, KKRMDLVLELKNNASKLLLAI, which constitutes a domain 5 sub-domain (D5SD) of IP3R-1 that specifically binds Lck via its SH2 domain. With the addition of an HIV-TAT sequence to enable cell permeability of D5SD peptide, we observed wide-spread, Ca2+-dependent, cell killing of hematological cancer cells when the Lck-IP3R PPI was disrupted by TAT-D5SD. All cell lines and primary cells were sensitive to D5SD peptide, but malignant T-cells were less sensitive compared with B-cell or myeloid malignancies. Mining of RNA-seq data showed that LCK was expressed in primary diffuse large B-cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML). In fact, LCK shows a similar pattern of expression as many well-characterized AML oncogenes and is part of a protein interactome that includes FLT3-ITD, Notch-1, and Kit. Consistent with these findings, our data suggest that the Lck-IP3R PPI may protect malignant hematopoietic cells from death. Importantly, TAT-D5SD showed no cytotoxicity in three different non-hematopoietic cell lines; thus its ability to induce cell death appears specific to hematopoietic cells. Together, these data show that a peptide designed to disrupt the Lck-IP3R PPI has a wide range of pre-clinical activity in leukemia and lymphoma.
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spelling pubmed-98826572023-01-28 A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma Harr, Michael Lavik, Andrew McColl, Karen Zhong, Fei Haberer, Ben Aldabbagh, Khadijah Yee, Vivien Distelhorst, Clark W. Res Sq Article There is increasing evidence that the T-cell protein, Lck, is involved in the pathogenesis of chronic lymphocytic leukemia (CLL) as well as other leukemias and lymphomas. We previously discovered that Lck binds to domain 5 of inositol 1,4,5-trisphosphate receptors (IP3R) to regulate Ca2+ homeostasis. Using bioinformatics, we targeted a region within domain 5 of IP3R-1 predicted to facilitate protein-protein interactions (PPIs). We generated a synthetic 21 amino acid peptide, KKRMDLVLELKNNASKLLLAI, which constitutes a domain 5 sub-domain (D5SD) of IP3R-1 that specifically binds Lck via its SH2 domain. With the addition of an HIV-TAT sequence to enable cell permeability of D5SD peptide, we observed wide-spread, Ca2+-dependent, cell killing of hematological cancer cells when the Lck-IP3R PPI was disrupted by TAT-D5SD. All cell lines and primary cells were sensitive to D5SD peptide, but malignant T-cells were less sensitive compared with B-cell or myeloid malignancies. Mining of RNA-seq data showed that LCK was expressed in primary diffuse large B-cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML). In fact, LCK shows a similar pattern of expression as many well-characterized AML oncogenes and is part of a protein interactome that includes FLT3-ITD, Notch-1, and Kit. Consistent with these findings, our data suggest that the Lck-IP3R PPI may protect malignant hematopoietic cells from death. Importantly, TAT-D5SD showed no cytotoxicity in three different non-hematopoietic cell lines; thus its ability to induce cell death appears specific to hematopoietic cells. Together, these data show that a peptide designed to disrupt the Lck-IP3R PPI has a wide range of pre-clinical activity in leukemia and lymphoma. American Journal Experts 2023-01-09 /pmc/articles/PMC9882657/ /pubmed/36711753 http://dx.doi.org/10.21203/rs.3.rs-2436910/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Harr, Michael
Lavik, Andrew
McColl, Karen
Zhong, Fei
Haberer, Ben
Aldabbagh, Khadijah
Yee, Vivien
Distelhorst, Clark W.
A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma
title A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma
title_full A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma
title_fullStr A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma
title_full_unstemmed A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma
title_short A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma
title_sort novel peptide that disrupts the lck-ip3r protein-protein interaction induces widespread cell death in leukemia and lymphoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882657/
https://www.ncbi.nlm.nih.gov/pubmed/36711753
http://dx.doi.org/10.21203/rs.3.rs-2436910/v1
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