Universität zu Köln

Schwamb, Janine, Feldhaus, Valeska, Baumann, Michael, Patz, Michaela, Brodesser, Susanne, Brinker, Reinhild, Claasen, Julia, Pallasch, Christian P. ORCID: 0000-0001-5675-6905, Hallek, Michael, Wendtner, Clemens-Martin and Frenzel, Lukas P. (2012). B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides. Blood, 120 (19). S. 3978 - 3986. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

Survival of chronic lymphocytic leukemia (CLL) cells is triggered by several stimuli, such as the B-cell receptor (BCR), CD40 ligand (CD40L), or interleukin-4 (IL-4). We identified that these stimuli regulate apoptosis resistance by modulating sphingolipid metabolism. Applying liquid chromatography electrospray ionization tandem mass spectrometry, we revealed a significant decrease of proapoptotic ceramide in BCR/IL-4/CD40L-stimulated primary CLL cells compared with untreated controls. Antiapoptotic glucosylceramide levels were significantly increased after BCR cross-linking. We identified BCR engagement to catalyze the crucial modification of ceramide to glucosylceramide via UDPglucose ceramide glucosyltransferase (UGCG). Besides specific UGCG inhibitors, our data demonstrate that IgM-mediated UGCG expression was inhibited by the novel and highly effective PI3K delta and BTK inhibitors CAL-101 and PCI-32765, which reverted IgM-induced resistance toward apoptosis of CLL cells. Sphingolipids were recently shown to be crucial for mediation of apoptosis via mitochondria. Our data reveal ABT-737, a mitochondria-targeting drug, as interesting candidate partner for PI3K delta and BTK inhibition, resulting in synergistic apoptosis, even under protection by the BCR. In summary, we identified the mode of action of novel kinase inhibitors CAL-101 and PCI-32765 by controlling the UGCG-mediated ceramide/glucosylceramide equilibrium as a downstream molecular switch of BCR signaling, also providing novel targeted treatment options beyond current chemotherapy-based regimens. (Blood. 2012;120(19):3978-3985)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schwamb, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Feldhaus, Valeska UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Patz, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Brodesser, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Brinker, Reinhild UNSPECIFIED UNSPECIFIED UNSPECIFIED Claasen, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Pallasch, Christian P. UNSPECIFIED orcid.org/0000-0001-5675-6905 UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Wendtner, Clemens-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Frenzel, Lukas P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-479077
DOI:	10.1182/blood-2012-05-431783
Journal or Publication Title:	Blood
Volume:	120
Number:	19
Page Range:	S. 3978 - 3986
Date:	2012
Publisher:	AMER SOC HEMATOLOGY
Place of Publication:	WASHINGTON
ISSN:	1528-0020
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; TYROSINE KINASE INHIBITOR; GLUCOSYLCERAMIDE SYNTHASE; CANCER-CELLS; MULTIDRUG-RESISTANCE; N-BUTYLDEOXYNOJIRIMYCIN; BIOACTIVE SPHINGOLIPIDS; MITOCHONDRIAL-MEMBRANE; LYMPHOID MALIGNANCIES; LIPOPROTEIN-LIPASE Multiple languages Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47907