IRON OVERLOAD-ASSOCIATED GENETIC INSTABILITY IN MYELODYSPLASTIC SYNDROME
(Abstract release date: 05/19/16)
EHA Library. Haase D. 06/09/16; 132751; E1202
Prof. Dr. Detlef Haase
Contributions
Contributions
Abstract
Abstract: E1202
Type: Eposter Presentation
Background
Not only clinical experience, but also numerous experimental and animal-modell studies demonstrated that iron overload (IO) negatively impacts on survival outcomes in patients suffering from myelodysplastic syndromes (MDS). However, the molecular mechanisms of IO induced genetic damage have neither been sufficiently demonstrated nor been fully understood.
Aims
We aimed to investigate the association between IO, measured as serum ferritin (SF) as suitable surrogate marker, and genetic instability, considered to be a main factor responsible for MDS progression to secondary acute myeloid leukemia (sAML).
Methods
We included 55 patients (median age 74 years, 62% males). The majority (n=50) had different MDS subtypes, 5 patients had myelodysplastic/myeloproliferative neoplasms (MSD/MPN). The patients were divided into two subgroups with normal and elevated SF levels, using 275 µg/l as cut-off for elevated SF. 26 patients showed normal SF levels (median: 65 µg/l, range: 8-256 µg/l), while 29 patients showed elevated SF levels (median: 1150 µg/l, range: 283-3872 µg/l). Various parameters for genetic instability were analyzed and statistically compared between the two subgroups with normal and elevated SF: a) molecular karyotyping (SNP array analysis) to determine the total genomic alterations (TGA) size, b) immunofluorescent determination of γH2AX-foci for quantifying DNA double-strand breaks (DSB) in CD34+ peripheral blood (PB) cells, c) telomere length (TL) of PB granulocytes and lymphocytes, and d) plasma nitric oxide metabolites as markers for oxidative stress.
Results
Subsequent analyses revealed a positive correlation of SF levels and bone marrow blast counts. Thus, all further analyses were adjusted by a logistic regression model for unevenly distributed blast counts. PB nitric oxide metabolites did not correlate with SF level (N=33 patients with available data). Iron overload measured by SF showed a significant correlation with the number of γH2AX-foci per CD34+ PB cell (r=0.481, p=0.039). The median number of γH2AX-foci per CD34+ PB cells was significantly highlower in 8 patients with normal SF as compared to 10 patients with elevated SF level (1.9 vs. 5.7 γH2AX-foci/CD34+ cell (adjusted p=0.050). TGA size was positively correlating with SF levels (r=0.397, p=0.026) and with marrow blast counts (r=0.381, p=0.077). TGA size was higher in 28 patients with elevated SF (median: 34 Mbp, range: 0-248 Mbp) as compared to 23 patients with normal SF (median: 0 Mbp, range: 0-155 Mbp, adjusted p>0.5). Telomere length and IO showed a significant negative correlation (r=-0.497, p=0.002). TL in granulocytes was significantly reduced in 13 patients with elevated SF (median: -1.61 kb, range: -4.06-1.31) as compared to 13 patients with normal SF levels (median: 0.48 kb, range: -3.13-5.32 kb, adjusted p=0.024). In contrast, lymphocyte TL was not influenced by the SF level.
Conclusion
In this study, IO was significantly associated with numerous markers of genetic instability. Elevated SF levels were promoting the TGA size, spontaneous nuclear damage assessed by γH2AX-foci and replicative stress (TL) in granulocytes representing the myeloid compartment, whereas the lymphocyte compartment remained uninfluenced by IO. These findings further support the assumption of IO being closely related to leukemic transformation in MDS. Our results contribute to explain the association of IO and disease progression found in several studies. Whether these results may have consequences for diagnostics and therapeutic decision-making in patients with MDS remains to be further investigated.
Session topic: E-poster
Keyword(s): Genetic instability, Iron overload, MDS
Type: Eposter Presentation
Background
Not only clinical experience, but also numerous experimental and animal-modell studies demonstrated that iron overload (IO) negatively impacts on survival outcomes in patients suffering from myelodysplastic syndromes (MDS). However, the molecular mechanisms of IO induced genetic damage have neither been sufficiently demonstrated nor been fully understood.
Aims
We aimed to investigate the association between IO, measured as serum ferritin (SF) as suitable surrogate marker, and genetic instability, considered to be a main factor responsible for MDS progression to secondary acute myeloid leukemia (sAML).
Methods
We included 55 patients (median age 74 years, 62% males). The majority (n=50) had different MDS subtypes, 5 patients had myelodysplastic/myeloproliferative neoplasms (MSD/MPN). The patients were divided into two subgroups with normal and elevated SF levels, using 275 µg/l as cut-off for elevated SF. 26 patients showed normal SF levels (median: 65 µg/l, range: 8-256 µg/l), while 29 patients showed elevated SF levels (median: 1150 µg/l, range: 283-3872 µg/l). Various parameters for genetic instability were analyzed and statistically compared between the two subgroups with normal and elevated SF: a) molecular karyotyping (SNP array analysis) to determine the total genomic alterations (TGA) size, b) immunofluorescent determination of γH2AX-foci for quantifying DNA double-strand breaks (DSB) in CD34+ peripheral blood (PB) cells, c) telomere length (TL) of PB granulocytes and lymphocytes, and d) plasma nitric oxide metabolites as markers for oxidative stress.
Results
Subsequent analyses revealed a positive correlation of SF levels and bone marrow blast counts. Thus, all further analyses were adjusted by a logistic regression model for unevenly distributed blast counts. PB nitric oxide metabolites did not correlate with SF level (N=33 patients with available data). Iron overload measured by SF showed a significant correlation with the number of γH2AX-foci per CD34+ PB cell (r=0.481, p=0.039). The median number of γH2AX-foci per CD34+ PB cells was significantly highlower in 8 patients with normal SF as compared to 10 patients with elevated SF level (1.9 vs. 5.7 γH2AX-foci/CD34+ cell (adjusted p=0.050). TGA size was positively correlating with SF levels (r=0.397, p=0.026) and with marrow blast counts (r=0.381, p=0.077). TGA size was higher in 28 patients with elevated SF (median: 34 Mbp, range: 0-248 Mbp) as compared to 23 patients with normal SF (median: 0 Mbp, range: 0-155 Mbp, adjusted p>0.5). Telomere length and IO showed a significant negative correlation (r=-0.497, p=0.002). TL in granulocytes was significantly reduced in 13 patients with elevated SF (median: -1.61 kb, range: -4.06-1.31) as compared to 13 patients with normal SF levels (median: 0.48 kb, range: -3.13-5.32 kb, adjusted p=0.024). In contrast, lymphocyte TL was not influenced by the SF level.
Conclusion
In this study, IO was significantly associated with numerous markers of genetic instability. Elevated SF levels were promoting the TGA size, spontaneous nuclear damage assessed by γH2AX-foci and replicative stress (TL) in granulocytes representing the myeloid compartment, whereas the lymphocyte compartment remained uninfluenced by IO. These findings further support the assumption of IO being closely related to leukemic transformation in MDS. Our results contribute to explain the association of IO and disease progression found in several studies. Whether these results may have consequences for diagnostics and therapeutic decision-making in patients with MDS remains to be further investigated.
Session topic: E-poster
Keyword(s): Genetic instability, Iron overload, MDS
Abstract: E1202
Type: Eposter Presentation
Background
Not only clinical experience, but also numerous experimental and animal-modell studies demonstrated that iron overload (IO) negatively impacts on survival outcomes in patients suffering from myelodysplastic syndromes (MDS). However, the molecular mechanisms of IO induced genetic damage have neither been sufficiently demonstrated nor been fully understood.
Aims
We aimed to investigate the association between IO, measured as serum ferritin (SF) as suitable surrogate marker, and genetic instability, considered to be a main factor responsible for MDS progression to secondary acute myeloid leukemia (sAML).
Methods
We included 55 patients (median age 74 years, 62% males). The majority (n=50) had different MDS subtypes, 5 patients had myelodysplastic/myeloproliferative neoplasms (MSD/MPN). The patients were divided into two subgroups with normal and elevated SF levels, using 275 µg/l as cut-off for elevated SF. 26 patients showed normal SF levels (median: 65 µg/l, range: 8-256 µg/l), while 29 patients showed elevated SF levels (median: 1150 µg/l, range: 283-3872 µg/l). Various parameters for genetic instability were analyzed and statistically compared between the two subgroups with normal and elevated SF: a) molecular karyotyping (SNP array analysis) to determine the total genomic alterations (TGA) size, b) immunofluorescent determination of γH2AX-foci for quantifying DNA double-strand breaks (DSB) in CD34+ peripheral blood (PB) cells, c) telomere length (TL) of PB granulocytes and lymphocytes, and d) plasma nitric oxide metabolites as markers for oxidative stress.
Results
Subsequent analyses revealed a positive correlation of SF levels and bone marrow blast counts. Thus, all further analyses were adjusted by a logistic regression model for unevenly distributed blast counts. PB nitric oxide metabolites did not correlate with SF level (N=33 patients with available data). Iron overload measured by SF showed a significant correlation with the number of γH2AX-foci per CD34+ PB cell (r=0.481, p=0.039). The median number of γH2AX-foci per CD34+ PB cells was significantly highlower in 8 patients with normal SF as compared to 10 patients with elevated SF level (1.9 vs. 5.7 γH2AX-foci/CD34+ cell (adjusted p=0.050). TGA size was positively correlating with SF levels (r=0.397, p=0.026) and with marrow blast counts (r=0.381, p=0.077). TGA size was higher in 28 patients with elevated SF (median: 34 Mbp, range: 0-248 Mbp) as compared to 23 patients with normal SF (median: 0 Mbp, range: 0-155 Mbp, adjusted p>0.5). Telomere length and IO showed a significant negative correlation (r=-0.497, p=0.002). TL in granulocytes was significantly reduced in 13 patients with elevated SF (median: -1.61 kb, range: -4.06-1.31) as compared to 13 patients with normal SF levels (median: 0.48 kb, range: -3.13-5.32 kb, adjusted p=0.024). In contrast, lymphocyte TL was not influenced by the SF level.
Conclusion
In this study, IO was significantly associated with numerous markers of genetic instability. Elevated SF levels were promoting the TGA size, spontaneous nuclear damage assessed by γH2AX-foci and replicative stress (TL) in granulocytes representing the myeloid compartment, whereas the lymphocyte compartment remained uninfluenced by IO. These findings further support the assumption of IO being closely related to leukemic transformation in MDS. Our results contribute to explain the association of IO and disease progression found in several studies. Whether these results may have consequences for diagnostics and therapeutic decision-making in patients with MDS remains to be further investigated.
Session topic: E-poster
Keyword(s): Genetic instability, Iron overload, MDS
Type: Eposter Presentation
Background
Not only clinical experience, but also numerous experimental and animal-modell studies demonstrated that iron overload (IO) negatively impacts on survival outcomes in patients suffering from myelodysplastic syndromes (MDS). However, the molecular mechanisms of IO induced genetic damage have neither been sufficiently demonstrated nor been fully understood.
Aims
We aimed to investigate the association between IO, measured as serum ferritin (SF) as suitable surrogate marker, and genetic instability, considered to be a main factor responsible for MDS progression to secondary acute myeloid leukemia (sAML).
Methods
We included 55 patients (median age 74 years, 62% males). The majority (n=50) had different MDS subtypes, 5 patients had myelodysplastic/myeloproliferative neoplasms (MSD/MPN). The patients were divided into two subgroups with normal and elevated SF levels, using 275 µg/l as cut-off for elevated SF. 26 patients showed normal SF levels (median: 65 µg/l, range: 8-256 µg/l), while 29 patients showed elevated SF levels (median: 1150 µg/l, range: 283-3872 µg/l). Various parameters for genetic instability were analyzed and statistically compared between the two subgroups with normal and elevated SF: a) molecular karyotyping (SNP array analysis) to determine the total genomic alterations (TGA) size, b) immunofluorescent determination of γH2AX-foci for quantifying DNA double-strand breaks (DSB) in CD34+ peripheral blood (PB) cells, c) telomere length (TL) of PB granulocytes and lymphocytes, and d) plasma nitric oxide metabolites as markers for oxidative stress.
Results
Subsequent analyses revealed a positive correlation of SF levels and bone marrow blast counts. Thus, all further analyses were adjusted by a logistic regression model for unevenly distributed blast counts. PB nitric oxide metabolites did not correlate with SF level (N=33 patients with available data). Iron overload measured by SF showed a significant correlation with the number of γH2AX-foci per CD34+ PB cell (r=0.481, p=0.039). The median number of γH2AX-foci per CD34+ PB cells was significantly highlower in 8 patients with normal SF as compared to 10 patients with elevated SF level (1.9 vs. 5.7 γH2AX-foci/CD34+ cell (adjusted p=0.050). TGA size was positively correlating with SF levels (r=0.397, p=0.026) and with marrow blast counts (r=0.381, p=0.077). TGA size was higher in 28 patients with elevated SF (median: 34 Mbp, range: 0-248 Mbp) as compared to 23 patients with normal SF (median: 0 Mbp, range: 0-155 Mbp, adjusted p>0.5). Telomere length and IO showed a significant negative correlation (r=-0.497, p=0.002). TL in granulocytes was significantly reduced in 13 patients with elevated SF (median: -1.61 kb, range: -4.06-1.31) as compared to 13 patients with normal SF levels (median: 0.48 kb, range: -3.13-5.32 kb, adjusted p=0.024). In contrast, lymphocyte TL was not influenced by the SF level.
Conclusion
In this study, IO was significantly associated with numerous markers of genetic instability. Elevated SF levels were promoting the TGA size, spontaneous nuclear damage assessed by γH2AX-foci and replicative stress (TL) in granulocytes representing the myeloid compartment, whereas the lymphocyte compartment remained uninfluenced by IO. These findings further support the assumption of IO being closely related to leukemic transformation in MDS. Our results contribute to explain the association of IO and disease progression found in several studies. Whether these results may have consequences for diagnostics and therapeutic decision-making in patients with MDS remains to be further investigated.
Session topic: E-poster
Keyword(s): Genetic instability, Iron overload, MDS
{{ help_message }}
{{filter}}