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Prepublished online as a Blood First Edition Paper on May 22, 2003; DOI 10.1182/blood-2003-03-0989.
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Blood, 15 September 2003, Vol. 102, No. 6, pp. 2146-2155
IMMUNOBIOLOGY
CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells
Silvia Deaglio,
Andrea Capobianco,
Luciana Bergui,
Jan Dürig,
Fortunato Morabito,
Ulrich Dührsen, and
Fabio Malavasi
From the Laboratory of Immunogenetics, Department of Genetics, Biology and Biochemistry, Research Center on Experimental Medicine (CeRMS), and the Department of Medicine and Experimental Oncology, University of Torino Medical School, Italy; Department of Hematology, University Hospital, Essen, Germany; and Bone Marrow Transplant Center, "Bianchi Melacrino Morelli" Hospital, Reggio Calabria, Italy.
The prognosis for patients with B-cell chronic lymphocytic leukemia (B-CLL) is generally less favorable for those expressing CD38. Our working hypothesis is that CD38 is not merely a marker in B-CLL, but that it plays a receptor role with pathogenetic potential ruling the proliferation of the malignant clone. CD38 levels were generally low in the patients examined and monoclonal antibody (mAb) ligation was inefficient in signaling. Other cellular models indicated that molecular density and surface organization are critical for CD38 functionality. Interleukin 2 (IL-2) induced a marked up-modulation and surface rearrangement of CD38 in all the patients studied. On reaching a specific expression threshold, CD38 becomes an efficient receptor in purified B-CLL cells. Indeed, mAb ligation is followed by Ca2+ fluxes and by a markedly increased proliferation. The unsuitability of CD38 to perform as a receptor is obviated through close interaction with the B-cell–receptor (BCR) complex and CD19. On mAb binding, CD38 translocates to the membrane lipid microdomains, as shown by a colocalization with the GM1 ganglioside and with CD81, a raft-resident protein. Finally, CD38 signaling in IL-2–treated B-CLL cells prolonged survival and induced the appearance of plasmablasts, providing a pathogenetic hypothesis for the occurrence of Richter syndrome.
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