PuSH - Publication Server of Helmholtz Zentrum München

Jensen, P.* ; Carlet, M. ; Schlenk, R.F.* ; Weber, A.* ; Kress, J.* ; Brunner, I.* ; Słabicki, M.* ; Grill, G.* ; Weisemann, S.* ; Cheng, Y.Y.* ; Jeremias, I. ; Scholl, C.* ; Fröhling, S.*

Requirement for LIM kinases in acute myeloid leukemia.

Leukemia 34, 3173–3185 (2020)
Postprint DOI PMC
Open Access Green
Free by publisher: Publ. Version/Full Text online available 07/2025
Acute myeloid leukemia (AML) is an aggressive disease for which only few targeted therapies are available. Using high-throughput RNA interference (RNAi) screening in AML cell lines, we identified LIM kinase 1 (LIMK1) as a potential novel target for AML treatment. HighLIMK1expression was significantly correlated with shorter survival of AML patients and coincided withFLT3mutations,KMT2Arearrangements, and elevatedHOXgene expression. RNAi- and CRISPR-Cas9-mediated suppression as well as pharmacologic inhibition of LIMK1 and its close homolog LIMK2 reduced colony formation and decreased proliferation due to slowed cell-cycle progression ofKMT2A-rearranged AML cell lines and patient-derived xenograft (PDX) samples. This was accompanied by morphologic changes indicative of myeloid differentiation. Transcriptome analysis showed upregulation of several tumor suppressor genes as well as downregulation of HOXA9 targets and mitosis-associated genes in response to LIMK1 suppression, providing a potential mechanistic basis for the anti-leukemic phenotype. Finally, we observed a reciprocal regulation between LIM kinases (LIMK) and CDK6, a kinase known to be involved in the differentiation block ofKMT2A-rearranged AML, and addition of the CDK6 inhibitor palbociclib further enhanced the anti-proliferative effect of LIMK inhibition. Together, these data suggest that LIMK are promising targets for AML therapy.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Gene-expression Profile; Cofilin Phosphorylation; Btg2 Expression; Cancer Cells; Target; Growth; Bin1; Identification; Metastasis; Mutations
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 34, Issue: , Pages: 3173–3185 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Macmillan Building, 4 Crinan St, London N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)