Michael Hallek / Phoung-Hien Nguyen - A 3

Comprehensive analyses of the mechanistic role of LYN kinase in B cell malignancies

Abstract

Chronic lymphocytic leukemia (CLL) is the most common B cell leukemia in the elderly. Survival of CLL cells tightly depends on a permissive tumor microenvironment composing of various soluble factors and cells of the niche. In-depth understanding and suitable modulation of the microenvironmental factors, besides targeting the leukemic cells directly, is vital for the success of CLL therapies. Lyn kinase is overexpressed and associated with apoptosis resistance of CLL cells. We recently showed that Lyn deficiency significantly hindered CLL development in vivo. Strikingly, loss of Lyn in the microenvironmental cells such as macrophages, but not within CLL cells, accounted for the strongly reduced leukemic progression.
Thus, we aim to further unveil the mechanistic role of LYN in B cell malignancies, in both tumor and microenvironmental cells. We will determine the cellular compartment of the CLL niche, in which Lyn expression is essential for supporting CLL progression, using a stem cell transplantation model and diverse coculture systems. Besides, we will study the contribution of Lyn-associated microenvironmental cells in Myc-induced lymphoma development in vivo. Finally, we will uncover the functional role of overexpressing Lyn observed in human CLL cells using a novel mouse model with B cell specific constitutively active Lyn mutation.

Clinical/medical relevance and sustainability in disease understanding

Collectively, our research will provide more insights into the mechanistic function of Lyn kinase in malignant B cells, as well as in microenvironmental cells. Our specific goals will foster a more complete understanding of the role of this kinase, as well as the mechanistic action of kinase inhibitors, formerly believed to target the leukemic cells. The overall goal is to facilitate new development of treatment combinations to create effective therapies for B cell malignancies.


Prof. Dr. med. Michael Hallek

Dept. I of Internal Medicine

Prof. Dr. med. Michael Hallek

Principal Investigator A 3
Executive Board Member

michael.hallek@uni-koeln.de

Work +49 221 478 4400

Fax (Work) +49 221 478 5455

Dept. I of Internal Medicine
Kerpener Str. 62
50937 Cologne

http://innere1.uk-koeln.de/team

Publications - Michael Hallek

Link to PubMed


Dr. rer. nat. Hien Nguyen

Dept. I for Internal Medicine

Dr. rer. nat. Hien Nguyen

Co-Principal Investigator A 3

hien.nguyen@uk-koeln.de

Work +49 221 478 84120

CECAD Research Center
Joseph-Stelzmann Str. 26
50931 Cologne

Publications - Hien Nguyen

Link to PubMed