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Expression patterns of microRNAs associated with CML phases and their disease related targets.

Machová Poláková K, Lopotová T, Klamová H, Burda P, Trněný M, Stopka T, Moravcová J - Mol. Cancer (2011)

Bottom Line: The expression deregulation of miR-150, miR-20a, miR-17, miR-19a, miR-103, miR-144, miR-155, miR-181a, miR-221 and miR-222 in CML was confirmed by real-time quantitative PCR.In silico analyses identified targeted genes of these miRNAs encoding proteins that are involved in cell cycle and growth regulation as well as several key signaling pathways such as of mitogen activated kinase-like protein (MAPK), epidermal growth factor receptor (EGFR, ERBB), transforming growth factor beta (TGFB1) and tumor protein p53 that are all related to CML.Decreased levels of miR-150 were detected in patients at diagnosis, in blast crisis and 67% of hematological relapses and showed significant negative correlation with miR-150 proved target MYB and with BCR-ABL transcript level.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Hematology and Blood Transfusion, Prague, U Nemocnice 1, 128 20, Czech Republic. katerina.machova@uhkt.cz

ABSTRACT

Background: MicroRNAs are important regulators of transcription in hematopoiesis. Their expression deregulations were described in association with pathogenesis of some hematological malignancies. This study provides integrated microRNA expression profiling at different phases of chronic myeloid leukemia (CML) with the aim to identify microRNAs associated with CML pathogenesis. The functions of in silico filtered targets are in this report annotated and discussed in relation to CML pathogenesis.

Results: Using microarrays we identified differential expression profiles of 49 miRNAs in CML patients at diagnosis, in hematological relapse, therapy failure, blast crisis and major molecular response. The expression deregulation of miR-150, miR-20a, miR-17, miR-19a, miR-103, miR-144, miR-155, miR-181a, miR-221 and miR-222 in CML was confirmed by real-time quantitative PCR. In silico analyses identified targeted genes of these miRNAs encoding proteins that are involved in cell cycle and growth regulation as well as several key signaling pathways such as of mitogen activated kinase-like protein (MAPK), epidermal growth factor receptor (EGFR, ERBB), transforming growth factor beta (TGFB1) and tumor protein p53 that are all related to CML. Decreased levels of miR-150 were detected in patients at diagnosis, in blast crisis and 67% of hematological relapses and showed significant negative correlation with miR-150 proved target MYB and with BCR-ABL transcript level.

Conclusions: This study uncovers microRNAs that are potentially involved in CML and the annotated functions of in silico filtered targets of selected miRNAs outline mechanisms whereby microRNAs may be involved in CML pathogenesis.

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Expression analysis of miR-150 (A.) and its target MYB (B.) in different phases of CML in comparison to control (CONT). CONT = 11, Dg = 13 diagnosis, AP/BC = 12 accelerated phase/blast crisis, Hr = 15 hematological relapse, TF = 14 therapy failure (failure to achieve complete cytogenetic remission), MMR = 16 major molecular response. *** P < 0.001;	 ** P < 0.01; * P < 0.05
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Figure 4: Expression analysis of miR-150 (A.) and its target MYB (B.) in different phases of CML in comparison to control (CONT). CONT = 11, Dg = 13 diagnosis, AP/BC = 12 accelerated phase/blast crisis, Hr = 15 hematological relapse, TF = 14 therapy failure (failure to achieve complete cytogenetic remission), MMR = 16 major molecular response. *** P < 0.001; ** P < 0.01; * P < 0.05

Mentions: Dramatic reduction of miR-150 in BC, at Dg and in Hr and its normal levels in patients under imatinib treatment (MMR and TF) (Figure 3) prompted us to determine this expression pattern on a larger cohort of patients (n = 70; Table 2). Significant down-regulation of the miRNA (p < 0.05) in comparison to healthy controls (n = 11) was confirmed for diagnosis and progressed phases of CML (Figure 4A.). MiR-150 level decreased more than 2-fold in 67% of hematological relapses (n = 10/15). There was no significant change in MMR and TF compared to controls. Among all patient samples analyzed, we found significant inverse correlation of miR-150 expression with BCR-ABL transcript level (p = 0.01; r = -0.501). To test whether miR-150 is regulated by BCR-ABL we have used a Ph+ cell line MOLM-7 and incubated it with two concentrations of imatinib (1uM and 10 uM, Additional file 2: Figure S1A) for total 48 hours. We observed that following reduction of BCR-ABL tyrosine kinase activity (exemplified by decreased intensity of p-CRKL (Additional file 2: Figure S1B)) by imatinib the miR-150 levels were significantly upregulated. This paragraph provides link between levels of one particular microRNA, miR-150, identified by our microarray analysis and CML pathogenesis.


Expression patterns of microRNAs associated with CML phases and their disease related targets.

Machová Poláková K, Lopotová T, Klamová H, Burda P, Trněný M, Stopka T, Moravcová J - Mol. Cancer (2011)

Expression analysis of miR-150 (A.) and its target MYB (B.) in different phases of CML in comparison to control (CONT). CONT = 11, Dg = 13 diagnosis, AP/BC = 12 accelerated phase/blast crisis, Hr = 15 hematological relapse, TF = 14 therapy failure (failure to achieve complete cytogenetic remission), MMR = 16 major molecular response. *** P < 0.001;	 ** P < 0.01; * P < 0.05
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3102634&req=5

Figure 4: Expression analysis of miR-150 (A.) and its target MYB (B.) in different phases of CML in comparison to control (CONT). CONT = 11, Dg = 13 diagnosis, AP/BC = 12 accelerated phase/blast crisis, Hr = 15 hematological relapse, TF = 14 therapy failure (failure to achieve complete cytogenetic remission), MMR = 16 major molecular response. *** P < 0.001; ** P < 0.01; * P < 0.05
Mentions: Dramatic reduction of miR-150 in BC, at Dg and in Hr and its normal levels in patients under imatinib treatment (MMR and TF) (Figure 3) prompted us to determine this expression pattern on a larger cohort of patients (n = 70; Table 2). Significant down-regulation of the miRNA (p < 0.05) in comparison to healthy controls (n = 11) was confirmed for diagnosis and progressed phases of CML (Figure 4A.). MiR-150 level decreased more than 2-fold in 67% of hematological relapses (n = 10/15). There was no significant change in MMR and TF compared to controls. Among all patient samples analyzed, we found significant inverse correlation of miR-150 expression with BCR-ABL transcript level (p = 0.01; r = -0.501). To test whether miR-150 is regulated by BCR-ABL we have used a Ph+ cell line MOLM-7 and incubated it with two concentrations of imatinib (1uM and 10 uM, Additional file 2: Figure S1A) for total 48 hours. We observed that following reduction of BCR-ABL tyrosine kinase activity (exemplified by decreased intensity of p-CRKL (Additional file 2: Figure S1B)) by imatinib the miR-150 levels were significantly upregulated. This paragraph provides link between levels of one particular microRNA, miR-150, identified by our microarray analysis and CML pathogenesis.

Bottom Line: The expression deregulation of miR-150, miR-20a, miR-17, miR-19a, miR-103, miR-144, miR-155, miR-181a, miR-221 and miR-222 in CML was confirmed by real-time quantitative PCR.In silico analyses identified targeted genes of these miRNAs encoding proteins that are involved in cell cycle and growth regulation as well as several key signaling pathways such as of mitogen activated kinase-like protein (MAPK), epidermal growth factor receptor (EGFR, ERBB), transforming growth factor beta (TGFB1) and tumor protein p53 that are all related to CML.Decreased levels of miR-150 were detected in patients at diagnosis, in blast crisis and 67% of hematological relapses and showed significant negative correlation with miR-150 proved target MYB and with BCR-ABL transcript level.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Hematology and Blood Transfusion, Prague, U Nemocnice 1, 128 20, Czech Republic. katerina.machova@uhkt.cz

ABSTRACT

Background: MicroRNAs are important regulators of transcription in hematopoiesis. Their expression deregulations were described in association with pathogenesis of some hematological malignancies. This study provides integrated microRNA expression profiling at different phases of chronic myeloid leukemia (CML) with the aim to identify microRNAs associated with CML pathogenesis. The functions of in silico filtered targets are in this report annotated and discussed in relation to CML pathogenesis.

Results: Using microarrays we identified differential expression profiles of 49 miRNAs in CML patients at diagnosis, in hematological relapse, therapy failure, blast crisis and major molecular response. The expression deregulation of miR-150, miR-20a, miR-17, miR-19a, miR-103, miR-144, miR-155, miR-181a, miR-221 and miR-222 in CML was confirmed by real-time quantitative PCR. In silico analyses identified targeted genes of these miRNAs encoding proteins that are involved in cell cycle and growth regulation as well as several key signaling pathways such as of mitogen activated kinase-like protein (MAPK), epidermal growth factor receptor (EGFR, ERBB), transforming growth factor beta (TGFB1) and tumor protein p53 that are all related to CML. Decreased levels of miR-150 were detected in patients at diagnosis, in blast crisis and 67% of hematological relapses and showed significant negative correlation with miR-150 proved target MYB and with BCR-ABL transcript level.

Conclusions: This study uncovers microRNAs that are potentially involved in CML and the annotated functions of in silico filtered targets of selected miRNAs outline mechanisms whereby microRNAs may be involved in CML pathogenesis.

Show MeSH
Related in: MedlinePlus