GFI136N as a therapeutic and prognostic marker for myelodysplastic syndrome

•GFI136N is present in about 9%–12% of all Caucasian patients with myelodysplastic syndrome.•GFI136N is an independent, adverse prognostic factor for survival.•GFI136N patients with myelodysplastic syndrome respond poorly to hypomethylating agents. Inherited gene variants play an important role in malignant diseases. The transcriptional repressor growth factor independence 1 (GFI1) regulates hematopoietic stem cell (HSC) self-renewal and differentiation. A single-nucleotide polymorphism of GFI1 (rs34631763) generates a protein with an asparagine (N) instead of a serine (S) at position 36 (GFI136N) and has a prevalence of 3%–5% among Caucasians. Because GFI1 regulates myeloid development, we examined the role of GFI136N on the course of MDS disease. To this end, we determined allele frequencies of GFI136N in four independent MDS cohorts from the Netherlands and Belgium, Germany, the ICGC consortium, and the United States. The GFI136N allele frequency in the 723 MDS patients genotyped ranged between 9% and 12%. GFI136N was an independent adverse prognostic factor for overall survival, acute myeloid leukemia-free survival, and event-free survival in a univariate analysis. After adjustment for age, bone marrow blast percentage, IPSS score, mutational status, and cytogenetic findings, GFI136N remained an independent adverse prognostic marker. GFI136S homozygous patients exhibited a sustained response to treatment with hypomethylating agents, whereas GFI136N patients had a poor sustained response to this therapy. Because allele status of GFI136N is readily determined using basic molecular techniques, we propose inclusion of GFI136N status in future prospective studies for MDS patients to better predict prognosis and guide therapeutic decisions. Inherited gene variants play an important role in malignant diseases. The transcriptional repressor growth factor independence 1 (GFI1) regulates hematopoietic stem cell (HSC) self-renewal and differentiation. A single-nucleotide polymorphism of GFI1 (rs34631763) generates a protein with an asparagine (N) instead of a serine (S) at position 36 (GFI136N) and has a prevalence of 3%–5% among Caucasians. Because GFI1 regulates myeloid development, we examined the role of GFI136N on the course of MDS disease. To this end, we determined allele frequencies of GFI136N in four independent MDS cohorts from the Netherlands and Belgium, Germany, the ICGC consortium, and the United States. The GFI136N allele frequency in the 723 MDS patients genotyped ranged between 9% and 12%. GFI136N was an independent adverse prognostic factor for overall survival, acute myeloid leukemia-free survival, and event-free survival in a univariate analysis. After adjustment for age, bone marrow blast percentage, IPSS score, mutational status, and cytogenetic findings, GFI136N remained an independent adverse prognostic marker. GFI136S homozygous patients exhibited a sustained response to treatment with hypomethylating agents, whereas GFI136N patients had a poor sustained response to this therapy. Because allele status of GFI136N is readily determined using basic molecular techniques, we propose inclusion of GFI136N status in future prospective studies for MDS patients to better predict prognosis and guide therapeutic decisions. GFI1 is a zinc finger transcriptional repressor that recruits histone-modifying enzymes, such as histone deacetylases, to the loci of its target genes [1Phelan J.D. Shroyer N.F. Cook T. Gebelein B. Grimes H.L. Gfi1-cells and circuits: Unraveling transcriptional networks of development and disease.Curr Opin Hematol. 2010; 17: 300-307Crossref PubMed Scopus (50) Google Scholar, 2Vvan der Meer L.T. Jansen J.H. van der Reijden B.A. Gfi1 and Gfi1b: Key regulators of hematopoiesis.Leukemia. 2010; 24: 1834-1843Crossref PubMed Scopus (143) Google Scholar]. GFI1 regulates the functions of hematopoietic stem cells (HSCs) [1Phelan J.D. Shroyer N.F. Cook T. Gebelein B. Grimes H.L. Gfi1-cells and circuits: Unraveling transcriptional networks of development and disease.Curr Opin Hematol. 2010; 17: 300-307Crossref PubMed Scopus (50) Google Scholar, 3Hock H. Hamblen M.J. Rooke H.M. et al.Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells.Nature. 2004; 431: 1002-1007Crossref PubMed Scopus (437) Google Scholar] as well as myeloid–lymphoid lineage decisions [4Person R.E. Li F.Q. Duan Z. et al.Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.Nat Genet. 2003; 34: 308-312Crossref PubMed Scopus (303) Google Scholar, 5Horman S.R. Velu C.S. Chaubey A. et al.Gfi1 integrates progenitor versus granulocytic transcriptional programming.Blood. 2009; 113: 5466-5475Crossref PubMed Scopus (54) Google Scholar]. A variant form of the GFI1 gene (denominated GFI136N) is associated with a predisposition to develop de novo acute myeloid leukemia (AML) [6Khandanpour C. Thiede C. Valk P.J. et al.A variant allele of growth factor independence 1 (GFI1) is associated with acute myeloid leukemia.Blood. 2010; 115: 2462-2472Crossref PubMed Scopus (39) Google Scholar], but it has also been reported to be involved in a case of neutropenia [7Hochberg J.C. Miron P.M. Hay B.N. et al.Mosaic tetraploidy and transient GFI1 mutation in a patient with severe chronic neutropenia.Pediatr Blood Cancer. 2008; 50: 630-632Crossref PubMed Scopus (9) Google Scholar]. Taking into consideration the predisposing role of GFI136N to de novo AML and its role in myeloid development, we investigated the role of GFI136N in myelodysplastic syndrome (MDS). All patient samples (peripheral blood [PB] or bone marrow [BM] aspirates) were obtained with informed consent according to the Declaration of Helsinki. The respective local ethics committees approved the use of all patient samples. The clinical characteristics of patients with a confirmed diagnosis of MDS used in this study have been previously described [8Makishima H. Yoshida K. Nguyen N. et al.Somatic SETBP1 mutations in myeloid malignancies.Nat Genet. 2013; 45: 942-946Crossref PubMed Scopus (193) Google Scholar, 9Langemeijer S.M. Kuiper R.P. Berends M. et al.Acquired mutations in TET2 are common in myelodysplastic syndromes.Nat Genet. 2009; 41: 838-842Crossref PubMed Scopus (619) Google Scholar, 10Papaemmanuil E. Gerstung M. Malcovati L. et al.Clinical and biological implications of driver mutations in myelodysplastic syndromes.Blood. 2013; 122 (quiz 3699): 3616-3627Crossref PubMed Scopus (1270) Google Scholar, 11Germing U. Lauseker M. Hildebrandt B. et al.Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study.Leukemia. 2012; 26: 1286-1292Crossref PubMed Scopus (100) Google Scholar, 12Platzbecker U. Al-Ali H.K. Gattermann N. et al.Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients.Leukemia. 2014; 28: 696-698Crossref PubMed Scopus (20) Google Scholar, 13Schanz J. Tuchler H. Sole F. et al.New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge.J Clin Oncol. 2012; 30: 820-829Crossref PubMed Scopus (526) Google Scholar]. Events in “event-free survival” were defined as death from any cause or progression of MDS to AML with blast counts higher than 20%. Overall survival events are defined as death from any cause. Bone marrow morphology studies were performed at individual centers. MDS was classified based on the World Health Organization (WHO) definition [14Harris N.L. Jaffe E.S. Diebold J. et al.World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.J Clin Oncol. 1999; 17: 3835-3849Crossref PubMed Scopus (2510) Google Scholar]. Genotyping was performed according to published procedures [6Khandanpour C. Thiede C. Valk P.J. et al.A variant allele of growth factor independence 1 (GFI1) is associated with acute myeloid leukemia.Blood. 2010; 115: 2462-2472Crossref PubMed Scopus (39) Google Scholar]. Significance of differences in percentages was determined using the two-sided, two-sample t test. Survival of the different human cohorts is based on the presence of GFI136N univariate analysis using Kaplan–Meier survival methods. Differences were assessed using the log-rank (Mantel–Cox) test. We used Cox proportional-hazards regression modeling to determine the influence of different factors with respect to survival. Factors taken into account were International Prognostic Scoring System (IPSS) risk group, BM blast count, age, sex, cytogenetic findings (based on IPSS classification), and in a last step, presence of GFI136N. Analyses were performed either separately (with each factor analyzed independently) or with the presence or absence of GFI136N. All p values reported are two-sided. Because of the exploratory nature of this study, no adjustment for multiple testing was done. All analyses presented were performed using GraphPad Prism 6 software (GraphPad Software, La Jolla, CA) or SPSS Version 19 (IBM, Armonk, NY). Between 9% and 12% of all adult MDS patients in four different Caucasian cohorts from Europe and the United States [8Makishima H. Yoshida K. Nguyen N. et al.Somatic SETBP1 mutations in myeloid malignancies.Nat Genet. 2013; 45: 942-946Crossref PubMed Scopus (193) Google Scholar, 9Langemeijer S.M. Kuiper R.P. Berends M. et al.Acquired mutations in TET2 are common in myelodysplastic syndromes.Nat Genet. 2009; 41: 838-842Crossref PubMed Scopus (619) Google Scholar, 10Papaemmanuil E. Gerstung M. Malcovati L. et al.Clinical and biological implications of driver mutations in myelodysplastic syndromes.Blood. 2013; 122 (quiz 3699): 3616-3627Crossref PubMed Scopus (1270) Google Scholar, 11Germing U. Lauseker M. Hildebrandt B. et al.Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study.Leukemia. 2012; 26: 1286-1292Crossref PubMed Scopus (100) Google Scholar, 12Platzbecker U. Al-Ali H.K. Gattermann N. et al.Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients.Leukemia. 2014; 28: 696-698Crossref PubMed Scopus (20) Google Scholar] were heterozygous for GFI136N, and only two patients from the European cohorts (and none of the U.S. cohort) were homozygous for GFI136N (Table 1). GFI136N allele frequency was higher among MDS patients than among the control cohort (3%–5%) as reported in our previous study regarding the role of GFI136N in de novo AML [15Khandanpour C. Krongold J. Schutte J. et al.The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.Blood. 2012; 120: 4006-4017Crossref PubMed Scopus (34) Google Scholar]. Although we did not determine the frequency of GFI136N among sex- and age-matched control subjects from every region, it is possible that GFI136N predisposes to MDS, similar to its predisposing role in de novo AML [15Khandanpour C. Krongold J. Schutte J. et al.The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.Blood. 2012; 120: 4006-4017Crossref PubMed Scopus (34) Google Scholar].Table 1Features of GFI136N- and GFI136S-carrying adult MDS patientsaGFI136N includes patients who are either homozygous or heterozygous for GFI136N and, thus, carrying one GFI136S allele. GFI136S refers to patients homozygous for GFI136S. Cytogenetic low risk: normal karyotype, 5q–, 20q–, –Y; poor risk: complex aberrations (≥3 anomalies), chromosome 7 anomalies; intermediate risk: all other aberrations. IPSS was based on Greenberg et al. [17]. Refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with excess blasts, type 1 (RAEB-1), refractory anemia with excess blasts, type 2 (RAEB-2), refractory cytopenia with multilineage dysplasia (RCMD), and MDS-unclassified (MDS-u) are based on the WHO definition for MDS. Standard errors of mean are given. Data for IPPS and cytogenetic classification are missing due to the lack of cytogenetic information on patients at the time of diagnosis. Data for histologic classification are missing because of the missing specification of MDS according to WHO criteria. The missing patients were diagnosed as having MDS according to the WHO definition. Student's t test was used to determine the significance of values, and two-sample t tests were used to determine the significance of differences between percentages. The different cohorts were independent of each other. No overlap exists with respect to samples. The numbers in parentheses correspond to the absolute numbers related to the indicated percentages.GFI136N (homo [2 patients]- or heterozygous)GFI136S (homozygozus)P value% All countries10 (n = 75)90 (n = 648)% United States11 (n = 30)89 (n = 254)% Germany9 (n = 20)91 (n = 193)% Netherlands and Belgium12 (n = 11)88 (n = 84)% ICGC11 (n = 14)89 (n = 117)Mean age66 ± 1.5 (n = 73)62 ± 0.6 (n = 638)0.01Gender (% male)64 (n = 47)66 (n = 426)0.7Blast percentage (BM) WHO9.4 ± 0.3 (n = 48)6.7 ± 1.1 (n = 464)0.01Hemoglobin (mg/dL)8.4 ± 0.5 (n = 24)8.1 ± 0.1 (n = 191)0.57Platelet count (1/nL)186 ± 37 (n = 24)177 ± 11 (n = 195)0.8Neutrophil count (1/nL)2.8 ± 0.8 (n = 24)2.7 ± 0.2 (n = 196)0.9Cytogenetic low risk (%)46 (n = 27)62 (n = 246)0.03Cytogenetic intermediate risk (%)14 (n = 8)16 (n = 64)0.5Cytogenetic high risk (%)41 (n = 24)24 (n = 96)0.006IPSS low (%)25 (n = 13)25 (n = 127)0.7IPSS intermediate 1 (%)40 (n = 38)42 (n = 323)0.7IPSS intermediate 2 (%)21 (n = 11)21 (n = 109)0.7IPSS high (%)15 (n = 8)10 (n = 52)0.255q– (%)5 (n = 2)4 (n = 13)0.8RA (%)0 (n = 0)9 (n = 30)0.054RARS+ RARST (%)11 (n = 4)9 (n = 28)0.7RAEB-1 (%)22 (n = 8)18 (n = 59)0.65RAEB-2 (%)39 (n = 15)22 (n = 69)0.02RAEB-1 + RAEB-2 (%)61 (23)40 (128)0.01RCMD (%)24 (n = 9)38 (n = 123)0.09MDS-u (%)01 (n = 4)0.5BM = bone marrow; ICGC = International Cancer Genome Consortium; WHO = World Health Organization.a GFI136N includes patients who are either homozygous or heterozygous for GFI136N and, thus, carrying one GFI136S allele. GFI136S refers to patients homozygous for GFI136S. Cytogenetic low risk: normal karyotype, 5q–, 20q–, –Y; poor risk: complex aberrations (≥3 anomalies), chromosome 7 anomalies; intermediate risk: all other aberrations. IPSS was based on Greenberg et al. 17Greenberg P. Cox C. LeBeau M.M. et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997; 89: 2079-2088Crossref PubMed Google Scholar. Refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with excess blasts, type 1 (RAEB-1), refractory anemia with excess blasts, type 2 (RAEB-2), refractory cytopenia with multilineage dysplasia (RCMD), and MDS-unclassified (MDS-u) are based on the WHO definition for MDS. Standard errors of mean are given. Data for IPPS and cytogenetic classification are missing due to the lack of cytogenetic information on patients at the time of diagnosis. Data for histologic classification are missing because of the missing specification of MDS according to WHO criteria. The missing patients were diagnosed as having MDS according to the WHO definition. Student's t test was used to determine the significance of values, and two-sample t tests were used to determine the significance of differences between percentages. The different cohorts were independent of each other. No overlap exists with respect to samples. The numbers in parentheses correspond to the absolute numbers related to the indicated percentages. Open table in a new tab BM = bone marrow; ICGC = International Cancer Genome Consortium; WHO = World Health Organization. We analyzed the effect of GFI136N on MDS disease course in two independent cohorts. Patients were recruited and treated either in the United States or in Europe. The European cohorts consisted of patients recruited and treated at different centers in Germany, Belgium, and The Netherlands [8Makishima H. Yoshida K. Nguyen N. et al.Somatic SETBP1 mutations in myeloid malignancies.Nat Genet. 2013; 45: 942-946Crossref PubMed Scopus (193) Google Scholar, 9Langemeijer S.M. Kuiper R.P. Berends M. et al.Acquired mutations in TET2 are common in myelodysplastic syndromes.Nat Genet. 2009; 41: 838-842Crossref PubMed Scopus (619) Google Scholar, 10Papaemmanuil E. Gerstung M. Malcovati L. et al.Clinical and biological implications of driver mutations in myelodysplastic syndromes.Blood. 2013; 122 (quiz 3699): 3616-3627Crossref PubMed Scopus (1270) Google Scholar, 11Germing U. Lauseker M. Hildebrandt B. et al.Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study.Leukemia. 2012; 26: 1286-1292Crossref PubMed Scopus (100) Google Scholar, 12Platzbecker U. Al-Ali H.K. Gattermann N. et al.Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients.Leukemia. 2014; 28: 696-698Crossref PubMed Scopus (20) Google Scholar]. The U.S. cohorts were referred to the Cleveland Clinic. In the two MDS cohorts from Europe and the United States, presence of GFI136N was associated with an inferior event-free survival rate (Fig. 1A, B). GFI136N also had a negative impact on overall survival (Fig. 1C, D) and on AML-free survival (data not shown). Next, we examined the association between GFI136N and established prognostic factors. GFI136N carriers were older, exhibited a tendency toward higher BM blast counts at diagnosis, were diagnosed with a more advanced stage of the disease according to histologic parameters, and had more adverse cytogenetic findings (Table 1). With respect to key blood parameters, no other differences between GFI136N and GFI136S carriers were observed (Table 1). and European GFI136S homozygous patients had of and and European GFI136N carriers had of and To more and to more we the U.S. and European cohorts. used to predict of MDS patients is based on IPSS H. J. et international prognostic scoring system for myelodysplastic syndromes.Blood. 2012; 120: PubMed Scopus Google Scholar, 17Greenberg P. Cox C. LeBeau M.M. et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997; 89: 2079-2088Crossref PubMed Google Scholar]. A of IPSS (denominated between more based on cytogenetic findings and H. J. et international prognostic scoring system for myelodysplastic syndromes.Blood. 2012; 120: PubMed Scopus Google Scholar]. not all of the for status were present in our we our on the of reported previously P. Cox C. LeBeau M.M. et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997; 89: 2079-2088Crossref PubMed Google Scholar], IPSS scoring event-free of GFI136S homozygous patients (Fig. the of the scoring GFI136N carriers had a event-free survival (Fig. among MDS patients in the low and intermediate 1 based on GFI136N carriers had a event-free (Fig. and AML-free survival (data not than GFI136S homozygous We also examined the association between allele status, cytogenetic findings and event-free survival. presence of GFI136N was associated with an inferior independent of the cytogenetic (Table 1). After for cytogenetic risk as one and and as a the presence of a GFI136N allele was to inferior event-free survival (Fig. in MDS patients with mutations or have an inferior prognosis K. et al.Clinical effect of mutations in myelodysplastic PubMed Scopus Google Scholar, B.A. et of a prognostic and the impact of mutations in patients with myelodysplastic Clin Oncol. 2012; 30: PubMed Scopus Google Scholar] (Fig. B). of GFI136N in the absence of or mutations had a similar effect on event-free survival as the presence of or mutations (Fig. the presence of a form of either or and a GFI136N allele had an adverse effect on event-free survival (Fig. analyses were not possible for mutations of or K. et al.Clinical effect of mutations in myelodysplastic PubMed Scopus Google Scholar, B.A. et of a prognostic and the impact of mutations in patients with myelodysplastic Clin Oncol. 2012; 30: PubMed Scopus Google Scholar], because of the of with or mutation and GFI136N. Because MDS patients who are or homozygous for GFI136N to be at diagnosis, have more adverse cytogenetic findings, and have a higher blast cell count at diagnosis, we examined the presence of GFI136N an adverse prognostic factor after for We that GFI136N was an independent after for the IPSS score, cytogenetic findings, and age, either or in at possible GFI136N accelerates AML development in MDS patients be based on our findings using We previously GFI136N or GFI136S instead of Gfi1 [15Khandanpour C. Krongold J. Schutte J. et al.The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.Blood. 2012; 120: 4006-4017Crossref PubMed Scopus (34) Google Scholar]. We reported that GFI136N is not to to its target genes to the as the more common GFI136S presence of one allele of GFI136N to higher of histone at at Gfi1 target to of genes development of myeloid [15Khandanpour C. Krongold J. Schutte J. et al.The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.Blood. 2012; 120: 4006-4017Crossref PubMed Scopus (34) Google Scholar], GFI136N accelerates AML development and We reported that a low of GFI1 the presence of GFI136N on a functional accelerates AML progression in different of one of MDS L. A. et as a prognostic and therapeutic factor for Scopus Google Scholar]. is not one changes the of and regarding to or with histone or 1 did not any differences between GFI136N and GFI136S [15Khandanpour C. Krongold J. Schutte J. et al.The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.Blood. 2012; 120: 4006-4017Crossref PubMed Scopus (34) Google Scholar] We also examined GFI136N predict response to therapy. To this in more we on patients that were treated with treatment is used for patients who are not for bone marrow or as a to a Key clinical after and treatment of myelodysplastic syndromes for better 2013; PubMed Scopus Google Scholar, in myelodysplastic syndromes.Blood. 2014; PubMed Scopus Google Scholar, C. we myelodysplastic syndromes.Blood. 2014; PubMed Scopus Google Scholar]. was no between GFI136N heterozygous carriers and GFI136S patients response to treatment with of GFI136S homozygous carriers with of GFI136N the response to treatment was in GFI136N carriers than in GFI136S homozygous carriers (Fig. is not because treatment with hypomethylating agents, such as not the of and in cells with a GFI136N allele [15Khandanpour C. Krongold J. Schutte J. et al.The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.Blood. 2012; 120: 4006-4017Crossref PubMed Scopus (34) Google Scholar]. The of GFI136N as a prognostic be in prospective studies and, the findings be the status of GFI136N be determined in MDS the role of GFI1 in myeloid development, GFI136N status also be of prognostic for patients with myeloproliferative diseases and chronic myeloid the frequency of GFI136N is also among patients with chronic myeloid In GFI136N be a therapeutic and prognostic for myeloid was a from the Germany, and the from the was a from the and a 1 and from the of Health and and are We the patients for consent to in the different studies and and for from and for from and survival regression for was defined in four different as published for intermediate intermediate = IPSS was defined in four different as published Open table in a new tab survival regression for key prognostic survival regression for age, blast count, sex, cytogenetic and as a last step, presence of GFI136N for more for (% intermediate intermediate = Cox survival regression for age, blast count, sex, cytogenetic and as a last step, presence of GFI136N for more Open table in a new tab = =

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