Leukemia & Lymphoma
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Is GDF15 beneficial to erythropoiesis in low grade myelodysplastic syndrome? Darren O'Toole, Paul Kennedy, John Quinn & Philip Thomas Murphy To cite this article: Darren O'Toole, Paul Kennedy, John Quinn & Philip Thomas Murphy (2015) Is GDF15 beneficial to erythropoiesis in low grade myelodysplastic syndrome?, Leukemia & Lymphoma, 56:6, 1914-1915, DOI: 10.3109/10428194.2014.977885 To link to this article: http://dx.doi.org/10.3109/10428194.2014.977885
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Accepted author version posted online: 27 Oct 2014. Published online: 14 Jan 2015. Submit your article to this journal
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [Washington University in St Louis]
Date: 05 November 2015, At: 17:18
Leukemia & Lymphoma, June 2015; 56(6): 1914–1915 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.977885
LETTER TO THE EDITOR
Is GDF15 beneficial to erythropoiesis in low grade myelodysplastic syndrome? Darren O’Toole, Paul Kennedy, John Quinn & Philip Thomas Murphy
Downloaded by [Washington University in St Louis] at 17:18 05 November 2015
Department of Haematology, Beaumont Hospital, Dublin, Ireland We were most interested in the recent publication by Cui et al. who measured serum growth-differentiation factor-15 (GDF15) as well as other serum markers of erythropoiesis and of iron metabolism in 107 subjects with myelodysplastic syndrome (MDS) not receiving red blood cell (RBC) transfusions [1]. In addition to reporting a weak negative correlation between GDF15 and the hepcidin–ferritin ratio, there was a positive correlation between serum GDF15 levels and percent of bone marrow erythroblasts. After ethics approval and informed written consent, we measured serum levels of GDF15, hepcidin, erythropoietin (EPO) and ferritin in 19 patients with low grade (International Prognostic Scoring System [IPSS] low-risk or intermediaterisk groups) MDS (refractory anemia with multilineage dysplasia, n ⫽ 15; refractory anemia with multilineage dysplasia and ring sideroblasts, n ⫽ 4) prior to starting recombinant EPO (R-EPO) (darbepoetin alfa 150 μg subcutaneous [SC] weekly) for anemia (hemoglobin [Hb] ⬍ 10 g/dL). We also re-measured serum GDF15 and hepcidin when patients had been on R-EPO for 8–12 weeks. Prior to starting R-EPO, we found no significant correlation between serum hepcidin and any other measured parameters, including the hepcidin–ferritin ratio. In fact, the only significant correlation between measured serum parameters was a negative correlation between serum GDF15 and serum EPO (Pearson correlation coefficient r ⫽ ⫺ 0.64, p ⫽ 0.00298; Figure 1). Based on modified International Working Group response criteria, patients with a satisfactory response to R-EPO (n ⫽ 12) had significantly lower serum EPO levels (mean ⫾ standard deviation [SD] ⫽ 50.9 ⫾ 42.7 mIU/mL) than non-responders (n ⫽ 7) (mean ⫾ SD ⫽ 191.5 ⫾ 179.6 mIU/mL) (unpaired t-test, two-tailed p ⫽ 0.019). There was also a significant increase in serum GDF15 (mean ⫾ SD ⫽ 1054 ⫾ 355 ng/mL) following R-EPO therapy, compared to pretreatment serum GDF15 (mean ⫾ SD ⫽ 906 ⫾ 379 ng/ mL) (paired t-test, two-tailed p ⫽ 0.0337). GDF15 is a member of the transforming growth factor-β super-family, conferring signaling by activation of Smad 1/5/8 or mitogen-activated protein kinase (p38-MAPK). Among hemopoietic cells, GDF15 is produced exclusively by eythroid precursors, is dependent on EPO and is essential for
normal erythropoiesis, as down-regulation inhibits erythroid differentiation [2]. Blood levels of GDF15 are increased in MDS and in other disorders characterized by intramedullary apoptosis of erythroblasts (ineffective erythropoiesis), but may also be elevated in cases of increased erythropoiesis associated with chronic hemolysis [3]. Patients with β-thalassemia syndromes have elevated serum GDF15 levels which contribute to iron overload by inhibiting hepcidin expression, but, based on our study findings and on the majority of published studies, GDF15 does not appear to be the major regulator of hepcidin expression in MDS. Although the numbers in our study are small, our finding that patients with higher serum GDF15 levels had lower serum EPO levels and, thus, a better Hb response to R-EPO suggests that GDF15 may have beneficial effects and not just reflect the degree of ineffective erythropoiesis in low grade MDS. In addition, the positive correlation, reported by Cui et al., between serum GDF15 levels and percent of bone marrow erythroblasts [1] suggests that GDF15 might be associated with a better preservation of erythropoiesis in low grade MDS, and thus a potentially better response to R-EPO. The possibility that GDF15 may confer beneficial effects on erythropoiesis in MDS, therefore, should prompt further investigation.
Figure 1. Correlation between serum erythropoietin and serum growth-differentiation factor-15 (GDF15) levels prior to darbepoetin alfa therapy.
Correspondence: Dr. Philip Thomas Murphy, MD, Beaumont Hospital, Department of Haematology, Beaumont Rd, Dublin 9, Ireland. E-mail: philipmurphy@ beaumont.ie Received 26 August 2014; accepted 13 October 2014
1914
Letter to the Editor 1915 Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References
Downloaded by [Washington University in St Louis] at 17:18 05 November 2015
[1] Cui R, Gale RP, Zhu G, et al. Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions. Leuk Res 2014;38:545–550.
[2] Ramirez J-M, Schaad O, Durual S, et al. Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts. Br J Haematol 2008;144:251–262. [3] Fertrin YF, Lanaro C, Franco-Penteado CF, et al. Erythropoiesisdriven regulation of hepcidin in human red cell disorders is better reflected through concentrations of soluble transferring receptor rather than growth differentiation factor 15. Am J Hematol 2014;89:385–390.
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Is GDF15 beneficial to erythropoiesis in low grade myelodysplastic syndrome? Darren O'Toole, Paul Kennedy, John Quinn & Philip Thomas Murphy To cite this article: Darren O'Toole, Paul Kennedy, John Quinn & Philip Thomas Murphy (2015) Is GDF15 beneficial to erythropoiesis in low grade myelodysplastic syndrome?, Leukemia & Lymphoma, 56:6, 1914-1915, DOI: 10.3109/10428194.2014.977885 To link to this article: http://dx.doi.org/10.3109/10428194.2014.977885
View supplementary material
Accepted author version posted online: 27 Oct 2014. Published online: 14 Jan 2015. Submit your article to this journal
Article views: 47
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [Washington University in St Louis]
Date: 05 November 2015, At: 17:18
Leukemia & Lymphoma, June 2015; 56(6): 1914–1915 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.977885
LETTER TO THE EDITOR
Is GDF15 beneficial to erythropoiesis in low grade myelodysplastic syndrome? Darren O’Toole, Paul Kennedy, John Quinn & Philip Thomas Murphy
Downloaded by [Washington University in St Louis] at 17:18 05 November 2015
Department of Haematology, Beaumont Hospital, Dublin, Ireland We were most interested in the recent publication by Cui et al. who measured serum growth-differentiation factor-15 (GDF15) as well as other serum markers of erythropoiesis and of iron metabolism in 107 subjects with myelodysplastic syndrome (MDS) not receiving red blood cell (RBC) transfusions [1]. In addition to reporting a weak negative correlation between GDF15 and the hepcidin–ferritin ratio, there was a positive correlation between serum GDF15 levels and percent of bone marrow erythroblasts. After ethics approval and informed written consent, we measured serum levels of GDF15, hepcidin, erythropoietin (EPO) and ferritin in 19 patients with low grade (International Prognostic Scoring System [IPSS] low-risk or intermediaterisk groups) MDS (refractory anemia with multilineage dysplasia, n ⫽ 15; refractory anemia with multilineage dysplasia and ring sideroblasts, n ⫽ 4) prior to starting recombinant EPO (R-EPO) (darbepoetin alfa 150 μg subcutaneous [SC] weekly) for anemia (hemoglobin [Hb] ⬍ 10 g/dL). We also re-measured serum GDF15 and hepcidin when patients had been on R-EPO for 8–12 weeks. Prior to starting R-EPO, we found no significant correlation between serum hepcidin and any other measured parameters, including the hepcidin–ferritin ratio. In fact, the only significant correlation between measured serum parameters was a negative correlation between serum GDF15 and serum EPO (Pearson correlation coefficient r ⫽ ⫺ 0.64, p ⫽ 0.00298; Figure 1). Based on modified International Working Group response criteria, patients with a satisfactory response to R-EPO (n ⫽ 12) had significantly lower serum EPO levels (mean ⫾ standard deviation [SD] ⫽ 50.9 ⫾ 42.7 mIU/mL) than non-responders (n ⫽ 7) (mean ⫾ SD ⫽ 191.5 ⫾ 179.6 mIU/mL) (unpaired t-test, two-tailed p ⫽ 0.019). There was also a significant increase in serum GDF15 (mean ⫾ SD ⫽ 1054 ⫾ 355 ng/mL) following R-EPO therapy, compared to pretreatment serum GDF15 (mean ⫾ SD ⫽ 906 ⫾ 379 ng/ mL) (paired t-test, two-tailed p ⫽ 0.0337). GDF15 is a member of the transforming growth factor-β super-family, conferring signaling by activation of Smad 1/5/8 or mitogen-activated protein kinase (p38-MAPK). Among hemopoietic cells, GDF15 is produced exclusively by eythroid precursors, is dependent on EPO and is essential for
normal erythropoiesis, as down-regulation inhibits erythroid differentiation [2]. Blood levels of GDF15 are increased in MDS and in other disorders characterized by intramedullary apoptosis of erythroblasts (ineffective erythropoiesis), but may also be elevated in cases of increased erythropoiesis associated with chronic hemolysis [3]. Patients with β-thalassemia syndromes have elevated serum GDF15 levels which contribute to iron overload by inhibiting hepcidin expression, but, based on our study findings and on the majority of published studies, GDF15 does not appear to be the major regulator of hepcidin expression in MDS. Although the numbers in our study are small, our finding that patients with higher serum GDF15 levels had lower serum EPO levels and, thus, a better Hb response to R-EPO suggests that GDF15 may have beneficial effects and not just reflect the degree of ineffective erythropoiesis in low grade MDS. In addition, the positive correlation, reported by Cui et al., between serum GDF15 levels and percent of bone marrow erythroblasts [1] suggests that GDF15 might be associated with a better preservation of erythropoiesis in low grade MDS, and thus a potentially better response to R-EPO. The possibility that GDF15 may confer beneficial effects on erythropoiesis in MDS, therefore, should prompt further investigation.
Figure 1. Correlation between serum erythropoietin and serum growth-differentiation factor-15 (GDF15) levels prior to darbepoetin alfa therapy.
Correspondence: Dr. Philip Thomas Murphy, MD, Beaumont Hospital, Department of Haematology, Beaumont Rd, Dublin 9, Ireland. E-mail: philipmurphy@ beaumont.ie Received 26 August 2014; accepted 13 October 2014
1914
Letter to the Editor 1915 Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References
Downloaded by [Washington University in St Louis] at 17:18 05 November 2015
[1] Cui R, Gale RP, Zhu G, et al. Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions. Leuk Res 2014;38:545–550.
[2] Ramirez J-M, Schaad O, Durual S, et al. Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts. Br J Haematol 2008;144:251–262. [3] Fertrin YF, Lanaro C, Franco-Penteado CF, et al. Erythropoiesisdriven regulation of hepcidin in human red cell disorders is better reflected through concentrations of soluble transferring receptor rather than growth differentiation factor 15. Am J Hematol 2014;89:385–390.
