Geldanamycin-induced Lyn dissociation from aberrant HSP90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia.

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Geldanamycin-induced Lyn dissociation from aberrant HSP90-stabilized cytosolic

complex is an early event in apoptotic mechanisms in B-chronic lymphocytic

leukemia.

Livio Trentin, a Frasson, Arianna Donella-Deana, Federica Frezzato,

A Pagano, Elena Tibaldi, Cristina Gattazzo, Renato Zambello, Gianpietro

Semenzato, and M Brunati

Blood, September 2, 2008; .

Department of Clinical and Experimental Medicine, Hematology and Clinical

Immunology Branch, Padua University School of Medicine, Padua, Italy.

Lyn, a tyrosine kinase belonging to the Src family, plays a key role as a switch

molecule that couples the B cell receptor to downstream signalling. In B-CLL

cells, Lyn is over-expressed, anomalously present in the cytosol and displays a

high constitutive activity, as compared to normal B lymphocytes. The aim of this

work was to gain insights into the molecular mechanisms underlying these

aberrant properties of Lyn, which have already been demonstrated to be related

to defective apoptosis in B-CLL cells. Herein, Lyn is described to be in an

active conformation as integral component of an aberrant cytosolic 600 kDa

multiprotein complex in B-CLL cells, associated with several proteins, such as

Hsp90 through its catalytic domain, and HS1 and SHP-1L through its SH3 domain.

In particular, Hsp90 appears tightly bound to cytosolic Lyn (CL), thus

stabilizing the aberrant complex and converting individual transient

interactions into stable ones. We also demonstrate that treatment of B-CLL cells

with geldanamycin, an Hsp90 inhibitor already reported to induce cell death, is

capable of dissociating the CL complex in the early phases of apoptosis and thus

inactivating CL itself. These data identify the CL complex as a potential target

for therapy in B-CLL.

PMID: 18768392