Universität zu Köln

Kohlhas, Viktoria, Hallek, Michael and Nguyen, Phuong-Hien (2020). Constitutive activation of Lyn kinase enhances BCR responsiveness, but not the development of CLL in E mu-TCL1 mice. Blood Adv., 4 (24). S. 6106 - 6117. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 2473-9537

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Abstract

The treatment of chronic lymphocytic leukemia (CLL) has been improved dramatically by inhibitors targeting B-cell receptor (BCR)-associated kinases. The tyrosine kinase Lyn is a key modulator of BCR signaling and shows increased expression and activity in CLL. To evaluate the functional relevance of Lyn for CLL, we generated a conditional knockin mouse model harboring a gain-of-function mutation of the Lyn gene (LynY508F), which was specifically expressed in the B-cell lineage (Lyn(up-B)). Kinase activity profiling revealed an enhanced responsiveness to BCR stimulation in Lyn(up-B) B cells. When crossing Lyn(up-B) mice with E mu-TCL1 mice (TCL1(tg/wt)), a transgenic mouse model for CLL, the resulting TCL1(tg/wt) Lyn(up-B) mice showed no significant change of hepatomegaly, splenomegaly, bone marrow infiltration, or overall survival when compared with TCL1(tg/wt) mice. Our data also suggested that TCL1 expression has partially masked the effect of the Lyn(up-B) mutation, because the BCR response was only slightly increased in TCL1(tg/wt) Lyn(up-B) compared with TCL1(tg/wt). In contrast, TCL1(tg/wt) Lyn(up-B) were protected at various degrees against spontaneous apoptosis in vitro and upon treatment with kinase inhibitors targeting the BCR. Collectively, and consistent with our previous data in a Lyn-deficient CLL model, these data lend further suggest that an increased activation of Lyn kinase in B cells does not appear to be a major driver of leukemia progression and the level of increased BCR responsiveness induced by Lyn(up-B) is insufficient to induce clear changes to CLL pathogenesis in vivo.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kohlhas, Viktoria UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Nguyen, Phuong-Hien UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-307557
DOI:	10.1182/bloodadvances.2020002584
Journal or Publication Title:	Blood Adv.
Volume:	4
Number:	24
Page Range:	S. 6106 - 6117
Date:	2020
Publisher:	AMER SOC HEMATOLOGY
Place of Publication:	WASHINGTON
ISSN:	2473-9537
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; KAPPA-B ACTIVATION; GAIN-OF-FUNCTION; TYROSINE KINASE; TUMOR-MICROENVIRONMENT; SUSTAINED ACTIVATION; IN-VITRO; CELLS; TCL1; INHIBITOR Multiple languages Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/30755