Contributions
Abstract: PB1934
Type: Publication Only
Background
The introduction of Imatinib and other Tyrosine Kinase inhibitors (TKIs) in the treatment of Chronic Myeloid Leukemia (CML) changed the course of this disease dramatically. Despite the higher therapeutic efficacy of different TKIs, CML cells develop mechanisms that overcome the therapeutic effect becoming resistant. The actual challenge is to predict which patients will develop resistance to TKIs, in order to improve therapeutic selection. Several mechanisms are described as necessary for resistant phenotypes, like BCR-ABL point mutation or overexpression, influx/efflux drug transporters expression (such as P-gP and OCT1), and alternative signaling pathways activation (like PI3K/Akt/mTOR). All these mechanisms are extremely controlled in cells, and microRNAs (miRs) are essential regulators of gene expression. In this context, the miRs profile could play a critical role in Imatinib response/resistance.
Aims
The aim of this work was investigated the role of miR-21, miR-519c, miR-451 and miR-26 expression levels in CML patients at diagnosis and correlated the expression levels of this miRs with Imatinib response.
Methods
For that, we assessed the expression levels of miR-203, miR-21, miR-519c, miR-451, miR-26 and miR-16 (endogenous control) by TaqMan MicroRNA Assays, in 29 CML patient samples at diagnosis. The study population presented a median of 53 years old, with 52% of males, and 86% of the patients were diagnosed at chronic phase. The proper statistical analysis was performed and was considered a significance levels of 95% (p<0.05).
Results
: The miR-451 was the miR with higher expression levels (median: 7.3), the miR-26 show a median of expression of 0.086, and the miR-21 presented the lowest levels (median: 0.0003). The expression of miR-519c was not detected in any sample. The expression levels of the evaluated miRs was independent of the phase of disease at diagnosis. Moreover, we evaluated the potential use of miRs expression as a biomarker of response to Imatinib at 6 and 12 months of treatment follow-up. The ROC analysis show that patients with miR-451 expression levels higher than 5.69 and lower expression levels of miR-21 than 1.16x10-4 have an optimal response to Imatinib at 12 months [AUC 0.77 (CI95% 0.58-0.95); Sensibility=92%; Specificity=64%; p=0,017; AUC 0.77 (CI95% 0.57-0.97); Sensibility=55%; Specificity=100%; p=0,021, respectively]. The patients with this profile combining miR-451 and miR-21 according to the cut-off levels have 44.8x higher probability of achieving an optimal response at 12 months. In opposition, patients with miR-451 expression levels lower than 5.69 and higher expression levels of miR-21 than 1.16x10-4 present 21.6 times lower probability to achieve an optimal response at the same time point.
Conclusion
Our preliminary results suggest that miRs profile in CML patients at diagnosis could constitute a new biomarker of Imatinib response, particularly the levels of miR-451/miR-21. However, more studies are necessary with a higher number of patients.
The work was supported by FMUC and Banco Santander Totta (FMUC-BST-2016-214), CIMAGO (Project 10/14) and FCT (SFRH/BD/51994/2012).
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, imatinib
Abstract: PB1934
Type: Publication Only
Background
The introduction of Imatinib and other Tyrosine Kinase inhibitors (TKIs) in the treatment of Chronic Myeloid Leukemia (CML) changed the course of this disease dramatically. Despite the higher therapeutic efficacy of different TKIs, CML cells develop mechanisms that overcome the therapeutic effect becoming resistant. The actual challenge is to predict which patients will develop resistance to TKIs, in order to improve therapeutic selection. Several mechanisms are described as necessary for resistant phenotypes, like BCR-ABL point mutation or overexpression, influx/efflux drug transporters expression (such as P-gP and OCT1), and alternative signaling pathways activation (like PI3K/Akt/mTOR). All these mechanisms are extremely controlled in cells, and microRNAs (miRs) are essential regulators of gene expression. In this context, the miRs profile could play a critical role in Imatinib response/resistance.
Aims
The aim of this work was investigated the role of miR-21, miR-519c, miR-451 and miR-26 expression levels in CML patients at diagnosis and correlated the expression levels of this miRs with Imatinib response.
Methods
For that, we assessed the expression levels of miR-203, miR-21, miR-519c, miR-451, miR-26 and miR-16 (endogenous control) by TaqMan MicroRNA Assays, in 29 CML patient samples at diagnosis. The study population presented a median of 53 years old, with 52% of males, and 86% of the patients were diagnosed at chronic phase. The proper statistical analysis was performed and was considered a significance levels of 95% (p<0.05).
Results
: The miR-451 was the miR with higher expression levels (median: 7.3), the miR-26 show a median of expression of 0.086, and the miR-21 presented the lowest levels (median: 0.0003). The expression of miR-519c was not detected in any sample. The expression levels of the evaluated miRs was independent of the phase of disease at diagnosis. Moreover, we evaluated the potential use of miRs expression as a biomarker of response to Imatinib at 6 and 12 months of treatment follow-up. The ROC analysis show that patients with miR-451 expression levels higher than 5.69 and lower expression levels of miR-21 than 1.16x10-4 have an optimal response to Imatinib at 12 months [AUC 0.77 (CI95% 0.58-0.95); Sensibility=92%; Specificity=64%; p=0,017; AUC 0.77 (CI95% 0.57-0.97); Sensibility=55%; Specificity=100%; p=0,021, respectively]. The patients with this profile combining miR-451 and miR-21 according to the cut-off levels have 44.8x higher probability of achieving an optimal response at 12 months. In opposition, patients with miR-451 expression levels lower than 5.69 and higher expression levels of miR-21 than 1.16x10-4 present 21.6 times lower probability to achieve an optimal response at the same time point.
Conclusion
Our preliminary results suggest that miRs profile in CML patients at diagnosis could constitute a new biomarker of Imatinib response, particularly the levels of miR-451/miR-21. However, more studies are necessary with a higher number of patients.
The work was supported by FMUC and Banco Santander Totta (FMUC-BST-2016-214), CIMAGO (Project 10/14) and FCT (SFRH/BD/51994/2012).
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, imatinib