Requirement for LIM Kinases in Acute Myeloid Leukemia

Overview

Journal Leukemia

Specialties Hematology
Oncology

Date 2020 Jun 28

PMID 32591645

Citations 6

Authors

Patrizia Jensen

Michela Carlet

Richard F Schlenk

Andrea Weber

Jana Kress

Ines Brunner

Mikolaj Slabicki

Gregor Grill

Simon Weisemann

Ya-Yun Cheng

Irmela Jeremias

Claudia Scholl

Stefan Frohling

Affiliations

Soon will be listed here.

Abstract

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. High LIMK1 expression was significantly correlated with shorter survival of AML patients and coincided with FLT3 mutations, KMT2A rearrangements, and elevated HOX gene 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 of KMT2A-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 of KMT2A-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.

Citing Articles

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development.

Li J, Kalev-Zylinska M Front Cell Dev Biol. 2023; 11:1170622.

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LIM Kinases, LIMK1 and LIMK2, Are Crucial Node Actors of the Cell Fate: Molecular to Pathological Features.

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Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive () Acute Lymphoblastic Leukemia (ALL).

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Liu X, Song Q, Wang D, Liu Y, Zhang Z, Fu W Oncol Lett. 2022; 24(1):234.

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