Beckmann, Laura ORCID: 0000-0001-5207-8991, Berg, Valeska, Dickhut, Clarissa, Sun, Clare ORCID: 0000-0001-8498-4729, Merkel, Olaf, Bloehdorn, Johannes ORCID: 0000-0003-1433-9702, Robrecht, Sandra, Seifert, Marc, Guerreiro, Alexandra da Palma, Claasen, Julia, Loroch, Stefan, Oliverio, Matteo, Underbayev, Chingiz, Vaughn, Lauren, Thomalla, Daniel, Huelsemann, Malte F., Tausch, Eugen, Fischer, Kirsten, Fink, Anna Maria ORCID: 0000-0002-7669-7890, Eichhorst, Barbara, Sickmann, Albert ORCID: 0000-0002-2388-5265, Wendtner, Clemens M., Stilgenbauer, Stephan, Hallek, Michael, Wiestner, Adrian, Zahedi, Rene P. and Frenzel, Lukas P. (2021). MARCKS affects cell motility and response to BTK inhibitors in CLL. Blood, 138 (7). S. 544 - 557. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Bruton tyrosine kinase (BTK) inhibitors are highly active drugs for the treatment of chronic lymphocytic leukemia (CLL). To understand the response to BTK inhibitors on a molecular level, we performed (phospho)proteomic analyses under ibrutinib treatment. We identified 3466 proteins and 9184 phosphopeptides (representing 2854 proteins) in CLL cells exhibiting a physiological ratio of phosphorylated serines (pS), threonines (pT), and tyrosines (pY) (pS:pT:pY). Expression of 83 proteins differed between unmutated immunoglobulin heavy-chain variable region (IGHV) CLL (UM-CLL) and mutated IGHV CLL (M-CLL). Strikingly, UM-CLL cells showed higher basal phosphorylation levels than M-CLL samples. Effects of ibrutinib on protein phosphorylation levels were stronger in UM-CLL, especially on phosphorylated tyrosines. The differentially regulated phosphopeptides and proteins clustered in pathways regulating cell migration, motility, cytoskeleton composition, and survival. One protein, myristoylated alanine-rich C-kinase substrate (MARCKS), showed striking differences in expression and phosphorylation level in UM-CLL vs M-CLL. MARCKS sequesters phosphatidylinositol-4,5-bisphosphate, thereby affecting central signaling pathways and clustering of the B-cell receptor (BCR). Genetically induced loss of MARCKS significantly increased AKT signaling and migratory capacity. CD40L stimulation increased expression of MARCKS. BCR stimulation induced phosphorylation of MARCKS, which was reduced by BTK inhibitors. In line with our in vitro findings, low MARCKS expression is associated with significantly higher treatment-induced leukocytosis and more pronounced decrease of nodal disease in patients with CLL treated with acalabrutinib.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Beckmann, LauraUNSPECIFIEDorcid.org/0000-0001-5207-8991UNSPECIFIED
Berg, ValeskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dickhut, ClarissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sun, ClareUNSPECIFIEDorcid.org/0000-0001-8498-4729UNSPECIFIED
Merkel, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bloehdorn, JohannesUNSPECIFIEDorcid.org/0000-0003-1433-9702UNSPECIFIED
Robrecht, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seifert, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerreiro, Alexandra da PalmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claasen, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loroch, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oliverio, MatteoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Underbayev, ChingizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaughn, LaurenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomalla, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huelsemann, Malte F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tausch, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, KirstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fink, Anna MariaUNSPECIFIEDorcid.org/0000-0002-7669-7890UNSPECIFIED
Eichhorst, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sickmann, AlbertUNSPECIFIEDorcid.org/0000-0002-2388-5265UNSPECIFIED
Wendtner, Clemens M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stilgenbauer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiestner, AdrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zahedi, Rene P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, Lukas P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-601164
DOI: 10.1182/blood.2020009165
Journal or Publication Title: Blood
Volume: 138
Number: 7
Page Range: S. 544 - 557
Date: 2021
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; TYROSINE KINASE INHIBITOR; B-CELLS; ELECTROSTATIC SEQUESTRATION; SAMPLE PREPARATION; ZAP-70 EXPRESSION; SURFACE IGM; T-CELLS; PROTEIN; IBRUTINIBMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60116

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