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Activation of signaling pathways in models of t(6;9)-acute myeloid leukemia

Chiriches, Claudia, Khan, Dilawar, Wieske, Maria, Guillen, Nathalie, Rokicki, Michal, Guy, Carol, Wilson, Marieangela, Heesom, Kate J., Ottmann, Oliver Gerhard and Ruthardt, Martin 2022. Activation of signaling pathways in models of t(6;9)-acute myeloid leukemia. Annals of Hematology 10.1007/s00277-022-04905-9

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Abstract

Patients within the WHO-subgroup of t(6;9)-positive acute myeloid leukemia (AML) differ from other AML subgroups as they are characterised by younger age and a grim prognosis. Leukemic transformation can often be attributed to single chromosomal aberrations encoding oncogenes, in the case of t(6;9)-AML to the fusion protein DEK-CAN (also called DEK-NUP214). As being a rare disease there is the urgent need for models of t(6;9)-AML. The only cell line derived from a t(6;9)-AML patient currently available is FKH1. By using phospho-proteomics on FKH1 cells, we found a strongly activated ABL1 kinase. Further investigation revealed the presence of ETV6-ABL1. This finding renders necessary to determine DEK-CAN- and ETV6-ABL1-related features when using FKH1. This can be done as ETV6-ABL1 activity in FKH1 is responsive to imatinib. Nevertheless, we provided evidence that both SFK and mTOR activation in FKH1 are DEK-CAN-related features as they were activated also in other t(6;9) and DEK-CAN-positive models. The activation of STAT5 previously shown to be strong in t(6;9)-AML and activated by DEK-CAN is regulated in FKH1 by both DEK-CAN and ETV6-ABL1. In conclusion, FKH1 cells still represent a model for t(6;9)-AML and could serve as model for ETV6-ABL1-positive AML if the presence of these leukemia-inducing oncogenes is adequately considered. Taken together, all our results provide clear evidence of novel and specific interdependencies between leukemia-inducing oncogenes and cancer signaling pathways which will influence the design of therapeutic strategies to better address the complexity of cancer signaling.

Item Type: Article
Date Type: Publication
Status: In Press
Schools: Medicine
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Publisher: Springer
ISSN: 0939-5555
Date of First Compliant Deposit: 11 August 2022
Date of Acceptance: 17 June 2022
Last Modified: 12 Aug 2022 09:04
URI: https://orca.cardiff.ac.uk/id/eprint/151862

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