Universität zu Köln

Niesen, Emanuel and Hallek, Michael (2019). New roles for B cell receptor associated kinases: when the B cell is not the target. Leukemia, 33 (3). S. 576 - 588. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5551

Full text not available from this repository.

Abstract

Targeting of B cell receptor associated kinases (BAKs), such as Bruton's tyrosine kinase (BTK) or phosphoinositol-3-kinase (PI3K) delta, by specific inhibitors has revolutionized the therapy of B lymphoid malignancies. BAKs are critical signaling transducers of BCR signaling and seem relevant in B cell lymphoma pathogenesis. The functional relevance of BTK for lymphoid malignancies is strongly supported by the observation that resistance to therapy in CLL patients treated with BTK inhibitors such as ibrutinib is often associated with mutations in genes coding for BTK or Phospholipase-C gamma (PLC.). In some contrast, next generation sequencing data show that BAKs are mutated at very low frequency in treatment-naive B cell lymphomas. Therefore, it remains debatable whether BAKs are essential drivers for lymphoma development. In addition, results obtained by targeted deletion of BAKs such as Lyn and Btk in murine CLL models suggest that BAKs may be essential to shape the dialogue between malignant B cells and the tumor microenvironment (TME). Since BAKs are expressed in multiple cell types, BAK inhibitors may disrupt the lymphoma supportive microenvironment. This concept also explains the typical response to BAK inhibitor treatment, characterized by a long-lasting increase of peripheral blood lymphoid cells, due to a redistribution from the lymphoid homing compartments. In addition, BAK inhibitors have shown some efficacy in solid tumors, probably through mediator cells in the TME. This review summarizes and validates the evidence for BAK inhibitors being part of a class of agents that modulate the (hematopoietic) microenvironment of cancers.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Niesen, Emanuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-155553
DOI:	10.1038/s41375-018-0366-8
Journal or Publication Title:	Leukemia
Volume:	33
Number:	3
Page Range:	S. 576 - 588
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5551
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; NF-KAPPA-B; BRUTONS TYROSINE KINASE; ANTIGEN RECEPTOR; TUMOR-MICROENVIRONMENT; THERAPEUTIC TARGET; ANTITUMOR ACTIVITIES; TRANSGENIC MOUSE; LIPID RAFTS; IBRUTINIB Multiple languages Oncology; Hematology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15555