BCR-ABL1-induced expression of HSPA8 promotes cell survival in chronic myeloid leukaemia.
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.
Foundation for Applied Medical Research, Division of Cancer, Area of Cell Therapy and Haematology Service, Clínica Universitaria, Universidad de Navarra, Spain.
Edurne San
ES
José-Enériz
José
J
Román-Gómez
Lucia
L
Cordeu
Esteban
E
Ballestar
Leire
L
Gárate
Enrique J
EJ
Andreu
Isabel
I
Isidro
Elizabeth
E
Guruceaga
Antonio
A
Jiménez-Velasco
Anabel
A
Heiniger
Antonio
A
Torres
Maria José
MJ
Calasanz
Manel
M
Esteller
Norma C
NC
Gutiérrez
Angel
A
Rubio
Ignacio
I
Pérez-Roger
Xabier
X
Agirre
Felipe
F
Prósper
D018952:Antigens, CD34 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000378:metabolism; D002470:Cell Survival; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D020869:Gene Expression Profiling; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D015398:Signal Transduction
D018952:Antigens, CD34; D056741:Cyclin D; D016213:Cyclins; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human