Lacramioara Botezatu, Lars C

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GFI136N as a therapeutic and prognostic marker for myelodysplastic syndrome Lacramioara Botezatu, Lars C. Michel, Hideki Makishima, Thomas Schroeder, Ulrich Germing, Rainer Haas, Bert van der Reijden, Anne E. Marneth, Saskia M. Bergevoet, Joop H. Jansen, Bartlomiej Przychodzen, Marcin Wlodarski, Charlotte Niemeyer, Uwe Platzbecker, Gerhard Ehninger, Ashwin Unnikrishnan, Dominik Beck, John Pimanda, Eva Hellström-Lindberg, Luca Malcovati, Jacqueline Boultwood, Andrea Pellagatti, Elli Papaemmanuil, Philipp Le Coutre, Jaspal Kaeda, Bertram Opalka, Tarik Möröy, Ulrich Dührsen, Jaroslaw Maciejewski, Cyrus Khandanpour Experimental Hematology Volume 44, Issue 7, Pages 590-595.e1 (July 2016) DOI: 10.1016/j.exphem.2016.04.001 Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Experimental Hematology 2016 44, 590-595. e1DOI: (10. 1016/j. exphem Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 1 Correlation between GFI136N and disease course of patients with MDS. (A) Patients from different European cohorts diagnosed with MDS on the basis of WHO criteria were genotyped with respect to the presence of GFI136N and examined with respect to median event-free survival (see also Methods); 95% confidence interval (CI) = 1.6–5.6. Median survival is indicated. (B) MDS Patients from a U.S. cohort diagnosed with MDS on the basis of WHO criteria were genotyped with respect to the presence of GFI136N and examined with respect to median event-free survival; 95% CI = 1.7–7.2. Median survival is indicated. (C) The same cohorts as in (A) were examined with respect to overall survival (death of any cause); 95% CI = 1.0–3.9. Median survival is indicated. (D) The same cohort as in (B) was examined with respect to overall survival (death from any cause) 95% CI = 1.5–5.8. Median survival is indicated. (E) Event-free survival of GFI136S homozygous patients was stratified based on IPSS classification. No sufficient follow-up was available for the International Cancer Genome Consortium (ICGC) patients. Follow-up is based on the patient cohorts from the United States, the Netherlands, Belgium, and Germany. Median survival is indicated. (F) Event-free survival of GFI136N homozygous or heterozygous patients was stratified based on IPSS classification. No sufficient follow up was available for the ICGC patients. Follow-up is based on the patient cohorts from the United States, the Netherlands, Belgium, and Germany. Median survival is indicated. (G) Event-free survival of patients (shown in A) classified as either IPSS subtype low or intermediate 1 (int-1) was stratified with respect to the presence of GFI136N; 95% CI = 1.4–6.2. (H) Patients from the U.S. and European cohorts with cytogenetic risk characteristics belonging to subtype “low” were stratified by the presence of GFI136N with respect to event-free survival; 95% CI = 1.5–5.7. Median survival is indicated. (I) Patients from the U.S. and European cohorts with cytogenetic risk characteristics belonging to subtype “intermediate” or “high” were stratified by presence of GFI136N with respect to event-free survival; 95% CI = 3.3–23.3. Median survival is indicated. Experimental Hematology 2016 44, 590-595.e1DOI: (10.1016/j.exphem.2016.04.001) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 2 Association between GFI136N, mutational status, prognosis, and therapeutic response. (A) Median event-free survival of patients based on mutational status of ASXL1; 95% confidence interval (CI) = 1.5–5.7. (B) Median event-free survival of patients based on mutational status of EZH2; 95% CI = 3.4–23.3. (C) Median event-free survival of patients based on presence of GFI136N and mutational status of ASXL1. (D) Median event-free survival of patients based on presence of GFI136N and mutational status of EZH2. (E) From the cohorts of patients treated in Europe and the United States, patients treated with 5-azacitidine were stratified with respect to GFI1 status. Presence of GFI136N was associated with a shorter response. Median survival is indicated; 95% CI = 1.1–10.5. Experimental Hematology 2016 44, 590-595.e1DOI: (10.1016/j.exphem.2016.04.001) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions