TY - JOUR
T1 - Tracking molecular relapse of chronic myeloid leukemia by measuring Hedgehog signaling status
AU - Cea, Michele
AU - Cagnetta, Antonia
AU - Cirmena, Gabriella
AU - Garuti, Anna
AU - Rocco, Ilaria
AU - Palermo, Claudia
AU - Pierri, Ivana
AU - Reverberi, Daniele
AU - Nencioni, Alessio
AU - Ballestrero, Alberto
AU - Gobbi, Marco
AU - Carella, Angelo Michele
AU - Patrone, Franco
PY - 2013/2
Y1 - 2013/2
N2 - Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of a leukemic stem cell (LSC) clone, carring a Philadelphia translocation, able to overcome the non-malignant hematopoietic stem cells. The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib are gold-standard for CML treatment. Each shows an impressive rate of complete cytogenetic response in chronic phase (CP)-CML. However, relapse and treatment failure are major problems with long-term use of TKIs. A polymerase chain reaction (PCR) assay to detect the mRNA expression of BCR-ABL1 represents the main molecular approach to monitoring response to treatment. However, using this analysis it is currently not possible to prospectively identify patients whose disease will relapse due to LSC reappearance. The aim of our study was to investigate whether the mRNA expression analysis of two Hedgehog (Hh) stemness signaling molecules, Smoothened (SMO) and Patched-1 (PTCH1), could predict upcoming molecular relapse. At the time of diagnosis, patients with high Sokal risk (n = 12) showed higher and lower levels of SMO and PTCH1, respectively (p = 0.0132), compared with patients with different Sokal scores (p = 0.0316 for intermediate risk and p = 0.0340 for low risk). These data suggest that Hh signaling was functionally more active in this risk group at the time of diagnosis. Furthermore, the kinetics of Hh signaling activity during the individual medical history correlated with BCR-ABL1 mRNA level and with upcoming molecular relapse. Also, mutation analysis of BCR-ABL1 revealed that activation of Hh signaling precedes molecular relapse by several months, mostly in patients carrying the gatekeeper mutation T315I. Importantly, in vitro data showed a synergistic effect of chemical inhibitors of Hh signaling and TKIs in both wild-type and resistant (T315I) CML cell lines. Collectively our data show that monitoring Hh pathway activity contemporaneously with BCR-ABL1 mRNA level may improve the chance of early detection of patients who will experience a relapse (mainly in the high Sokal risk group), paving the way for an innovative management of this hematologic malignancy.
AB - Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of a leukemic stem cell (LSC) clone, carring a Philadelphia translocation, able to overcome the non-malignant hematopoietic stem cells. The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib are gold-standard for CML treatment. Each shows an impressive rate of complete cytogenetic response in chronic phase (CP)-CML. However, relapse and treatment failure are major problems with long-term use of TKIs. A polymerase chain reaction (PCR) assay to detect the mRNA expression of BCR-ABL1 represents the main molecular approach to monitoring response to treatment. However, using this analysis it is currently not possible to prospectively identify patients whose disease will relapse due to LSC reappearance. The aim of our study was to investigate whether the mRNA expression analysis of two Hedgehog (Hh) stemness signaling molecules, Smoothened (SMO) and Patched-1 (PTCH1), could predict upcoming molecular relapse. At the time of diagnosis, patients with high Sokal risk (n = 12) showed higher and lower levels of SMO and PTCH1, respectively (p = 0.0132), compared with patients with different Sokal scores (p = 0.0316 for intermediate risk and p = 0.0340 for low risk). These data suggest that Hh signaling was functionally more active in this risk group at the time of diagnosis. Furthermore, the kinetics of Hh signaling activity during the individual medical history correlated with BCR-ABL1 mRNA level and with upcoming molecular relapse. Also, mutation analysis of BCR-ABL1 revealed that activation of Hh signaling precedes molecular relapse by several months, mostly in patients carrying the gatekeeper mutation T315I. Importantly, in vitro data showed a synergistic effect of chemical inhibitors of Hh signaling and TKIs in both wild-type and resistant (T315I) CML cell lines. Collectively our data show that monitoring Hh pathway activity contemporaneously with BCR-ABL1 mRNA level may improve the chance of early detection of patients who will experience a relapse (mainly in the high Sokal risk group), paving the way for an innovative management of this hematologic malignancy.
KW - Chronic myeloid leukemia
KW - Leukemic stem cell
KW - Molecular monitoring
KW - Resistance to treatment
UR - http://www.scopus.com/inward/record.url?scp=84872045017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872045017&partnerID=8YFLogxK
U2 - 10.3109/10428194.2012.708752
DO - 10.3109/10428194.2012.708752
M3 - Article
C2 - 22762548
AN - SCOPUS:84872045017
VL - 54
SP - 342
EP - 352
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
SN - 1042-8194
IS - 2
ER -