Chronic myeloid leukaemia Signal transduction HSPA8 CD34+
San José-Enériz, E., Román-Gómez, J., Cordeu, L. , Ballestar, E. et al. Br. j. haematol. 2008; 142: 571–582
In order to determine new signal transduction pathways implicated in
chronic myeloid leukaemia (CML), we performed a gene expression profile
comparison between CD34+ cells from CML patients and healthy donors.
Functional studies were performed using the Mo7e and Mo7e-p210 cell lines.
Expression of CCND1 (Cyclin D1), as well as the chaperone HSPA8, which is
important for regulation of CCND1, were significantly upregulated in CD34+
CML cells. Upregulation of HSPA8 was dependent, at least in part, on STAT5
(signal transducer and activator of transcrition 5)-dependent transcriptional
activation, as demonstrated by chromatin immunoprecipitation. The
presence of HSPA8 in the nuclear protein fraction as well as its binding to
CCND1 suggests that it may contribute to stabilization of the CCND1/CDK4
complex, which, in turn, may participate in proliferation of CML
cells. Treatment of CML cells with the specific HSPA8 inhibitor
15-deoxyspergualin induced inhibition of CML cell viability but did not
induce apoptosis. In conclusion, our studies suggest that STAT5-mediated
activation of HSPA8 induces nuclear translocation and activation of the
CCND1/CDK4 complex leading to increased proliferation of CML cells,
deciphering a new pathway implicated in CML and supporting a potential
role of chaperone inhibitors in the treatment of CML.