Reversible erythrocyte skeleton destabilization is modulated by beta-spectrin phosphorylation in childhood leukemia

The erythrocyte skeleton plays an essential role in determining the shape a nd deformability of the red cell. Disruption of the interaction between com ponents of the red cell membrane skeleton may cause loss of structural and functional integrity of the membrane. Several observations based on studies in vitro strongly suggest that phosphorylation may modify interactions bet ween proteins, leading to a reduced affinity. In particular, increased phos phorylation of beta -spectrin decreases membrane mechanical stability, In o rder to investigate the presence of membrane protein defects we investigate d the erythrocyte membrane protein composition and phosphorylation in 22 ch ildren with leukemia at diagnosis and during the remission phase. Sixteen c hildren had acute lymphoblastic leukemia (ALL), three had chronic myeloid l eukemia (CML) and three had acute myeloid leukemia (AML), Ten patients (eig ht ALL and two CML) displayed elliptocytosis and poikilocytosis, an increas e of spectrin dimers (41.8 +/- 15.6) and an enhanced phosphorylation of bet a -spectrin (108 +/- 15%) at diagnosis. These alterations disappeared durin g the remission phase. This is the first demonstration of a reversible eryt hrocyte membrane alteration in leukemia. Since the beta -spectrin phosphate sites are located near the C-terminal region and close to the head of the beta -chain that is involved in dimer-dimer interaction, we supposed that t he beta -chain phosphorylation has an effect upon the interactions between spectrin dimers, ie the tetramerization process. The weakening of this proc ess should be responsible for the presence of elliptocytes and poikilocytes as reported in hereditary elliptocytosis and pyropoikilocytosis.