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Letters to the Editor
Supplementary Table S12). In concordance with our path- way analysis, which showed upregulation of the STAT5 pathway in NUP98-KDM5A+ AML as compared to other types of AML and downregulation in NUP98-NSD1+ AML, the PI3K inhibitor omipalisib decreased cell viabil- ity in NUP98-KDM5A+ cases with a half maximal inhibitory concentration (IC50) of 1.6 nM - 2.2 nM), whereas it had little effect on NUP98-NSD1+ cases (IC50= 95.4 nM - 3000 nM) (Figure 2C). Trametinib, a MEK inhibitor with a manageable safety profile in pediatric patients, produced variable responses in both tested NUP98 fusions, but in all cases had an IC50 value of less than ~300 nM (Figure 2D)12. Both NUP98-fusion types responded to drugs targeting BRD4, CDK9 and HSP90, highlighting that the fusions do not solely have distinc- tive features but also common leukemia hallmarks (Figure 2E-G). Although these compounds produce prom- ising in vitrro responses, implementation in pediatric AML first awaits testing in phase I/II trials in adults. Furthermore, in vivo drug testing is required as in vitro response does not always imply in vivo response.13
Overall, these data show the value of including screen- ing for NUP98-KDM5A rearrangements as part of the standard survey in children with AML irrespectively of their AML FAB subtype. Although HSCT in first com- plete remission did not seem to prevent relapse in these cases, HSCT is currently the most effective post-remis- sion therapy for preventing relapse. Therefore, we sug- gest that NUP98-KDM5A+ AML deserves stratification into the high-risk group, and that HSCT in first complete remission should be considered. We showed that NUP98-KDM5A+ and NUP98-NSD1+ cases of AML have different clinical and biological characteristics, and may benefit from different types of targeted treatment.
Sanne Noort,1* Priscilla Wander,1,2* Todd A. Alonzo,3,4 Jenny Smith,5 Rhonda E. Ries,5 Robert B. Gerbing,3
M. Emmy M. Dolman,2 Franco Locatelli,6 Dirk Reinhardt,7 Andre Baruchel,8 Jan Stary,9 Jan J. Molenaar,2
Ronald W. Stam,2 Marry M. van den Heuvel-Eibrink,1,2
C. Michel Zwaan1,2,10 and Soheil Meshinchi5,11
1Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital Rotterdam, the Netherlands; 2Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; 3Children's Oncology Group, Monrovia, CA, USA; 4Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 5Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 6IRCCS Ospedale Bambino Gesù, Sapienza, University of Rome, Rome, Italy; 7AML-BFM
Study Group, Pediatric Hematology and Oncology, Essen, Germany; 8Pediatric Hematology-Immunology Department, University Hospital Robert Debré and Paris Diderot University, Paris, France; 9Czech Pediatric Hematology/Oncology (CPH), University Hospital Motol and Charles University, Prague, Czech Republic; 10Dutch Childhood Oncology Group (DCOG), The Hague, the Netherlands and 11Department of Pediatrics, Seattle Children's Hospital, University
of Washington, Seattle, WA, USA.
*SN and PW contributed equally as co-first authors.
Correspondence:
SOHEIL MESHINCHI - smeshinc@fhcrc.org
doi:10.3324/haematol.2019.236745 Disclosures: no conflicts of interests to disclose.
Contributions: SN and PW contributed equally to this work;
SN, PW, RWS, CMZ, MMvdH-E and SM designed the study; TAA., RBG, FL, DR, AB, JS, JJM, RWS and CMZ contributed materials and clinical data; PW, MEMD and SN performed the experiments; SN, PW, TAA, JS, RER, RBG, RWS, MMvdH-E, CMZ and SM analyzed data; SN, PW, TAA, JSRER and RBG performed the statistical analysis; SN, PW, RWS, CMZ, MMvdH-E and SM wrote the paper; SM, RWS, CMZ and MMvdH-E supervised the study; and all coauthors critically reviewed the manu- script and gave their final approval.
Acknowledgments: the authors would like to thank Sandra Mimoso Pinhanços, Bianca Koopmans, Luke Jones, Susan Arentsen-Peters and Patricia Garrido Castro for their assistance in the in vitro drug screens and validation.
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