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Open Access 08-08-2022 | Acute Myeloid Leukemia | Original Article

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

Authors: Claudia Chiriches, Dilawar Khan, Maria Wieske, Nathalie Guillen, Michal Rokicki, Carol Guy, Marieangela Wilson, Kate J. Heesom, Oliver Gerhard Ottmann, Martin Ruthardt

Published in: Annals of Hematology | Issue 10/2022

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.

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Title: Activation of signaling pathways in models of t(6;9)-acute myeloid leukemia
Authors: Claudia Chiriches
Dilawar Khan
Maria Wieske
Nathalie Guillen
Michal Rokicki
Carol Guy
Marieangela Wilson
Kate J. Heesom
Oliver Gerhard Ottmann
Martin Ruthardt
Publication date: 08-08-2022
Publisher: Springer Berlin Heidelberg
Keywords: Acute Myeloid Leukemia
Dasatinib
Imatinib
Leukemia
Published in: Annals of Hematology / Issue 10/2022
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-022-04905-9

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