Open AccessKnockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance
Author(s) -
Herrmann Andreas B.,
Müller MarthaLena,
Orth Martin F.,
Müller Jörg P.,
Zernecke Alma,
Hochhaus Andreas,
Ernst Thomas,
Butt Elke,
Frietsch Jochen J.
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14910
Subject(s) - cancer research , cell growth , biology , chemokine , tyrosine kinase , chemokine receptor , k562 cells , stem cell , dasatinib , carcinogenesis , abl , immunology , myeloid leukemia , microbiology and biotechnology , imatinib , leukemia , signal transduction , cancer , immune system , biochemistry , genetics
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR‐ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR‐ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1‐mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of LASP1 on processes involved in progression and maintenance of CML was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of LASP1 contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562 CML cells. Furthermore, LASP1 depletion in K562 CML cells leads to decreased cytokine release and reduced NK cell‐mediated cytotoxicity towards CML cells. Taken together, these results indicate that in CML, reduced levels of LASP1 alone and in combination with high CXCR4 expression may contribute to TKI resistance.