CXCL4 Antagonist May Have Role in Treating CLL

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[sounds hopeful]

Blood First Edition Paper, prepublished online May 19, 2005

Submitted January 4, 2005

Accepted May 9, 2005

Small peptide inhibitors of the CXCR4 chemokine receptor (CD184)

antagonize the activation, migration and antiapoptotic responses of

CXCL12 in chronic lymphocytic leukemia B cells

Meike Burger, Tanja Hartmann, Myriam Krome, Justyna Rawluk, Hirokazu

Tamamura, Nobutaka Fujii, J Kipps, and Jan A Burger*

Division of Hematology/Oncology, Department of Medicine, Freiburg

University Hospital, Freiburg, Germany

Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

Division of Hematology/Oncology, Department of Medicine, University of

California, San Diego, California, USA

Growth and survival of chronic lymphocytic leukemia (CLL) B cells are

favored by interactions between CLL B cells and nontumoral accessory

cells.

CLL B cells express high levels of CXCR4 chemokine receptors (CD184)

that direct leukemia cell chemotaxis. Marrow stromal cells or

nurselike cells (NLC) constitutively secrete CXCL12, the ligand for

CXCR4, thereby attract CLL B cells, and rescue CLL cells from

apoptosis in a contact-dependent fashion. The CXCR4-CXCL12 axis

therefore represents a potential therapeutic target in patients with

this disease.

We evaluated the most active CXCR4-specific antagonist T140, and its

analogs TC14012, and TN14003 for their relative capacity to inhibit

CXCL12 responses in CLL cells. T140, or its analogs, inhibited actin

polymerization, leukemia-cell chemotaxis, and migration of CLL cells

beneath marrow stromal cells. CXCL12-induced phosphorylation of p44/42

MAP kinase-(ERK1/2) and STAT3 phosphorylation was abolished by

pre-treatment of CLL cells with such CXCR4 antagonists.

TC14012 and TN14003 antagonized the anti-apoptotic effect of synthetic

CXCL12 and stromal cell-mediated protection of CLL cells from

spontaneous apoptosis. Furthermore, we found that culture of CLL cells

on marrow stromal cells protected CLL cells from chemotherapy-induced

apoptosis.

Treatment with CXCR4 antagonists re-sensitized CLL cells cultured with

stromal cells to fludarabine monophosphate-induced apoptosis.

These findings demonstrate that CXCR4 blocking agents effectively

antagonize CXCL12-induced migratory and signaling responses, and

stromal protection of CLL cells from spontaneous or

fludarabine-monophosphate induced apoptosis.

As such, small molecular CXCR4 antagonits alone or in combination with

other agents may have activity in the treatment of patients with this

disease.