Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure
Clonal evolution is believed to be a main driver for progression of various types of cancer and implicated in facilitating resistance to drugs. However, the hierarchical organization of malignant clones in the hematopoiesis of myelodysplastic syndromes (MDS) and its impact on response to drug therap...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
June 6, 2016
|
| In: |
Blood
Year: 2016, Volume: 128, Issue: 9, Pages: 1246-1259 |
| ISSN: | 1528-0020 |
| DOI: | 10.1182/blood-2015-11-679167 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1182/blood-2015-11-679167 Verlag, Volltext: http://www.bloodjournal.org.ezproxy.medma.uni-heidelberg.de/content/128/9/1246 
|
| Author Notes: | Maximilian Mossner, Johann-Christoph Jann, Janina Wittig, Florian Nolte, Stephanie Fey, Verena Nowak, Julia Obländer, Jovita Pressler, Iris Palme, Christina Xanthopoulos, Tobias Boch, Georgia Metzgeroth, Henning Röhl, Stephanie H. Witt, Helene Dukal, Corinna Klein, Steffen Schmitt, Patrick Gelß, Uwe Platzbecker, Ekaterina Balaian, Alice Fabarius, Helmut Blum, Torsten J. Schulze, Manja Meggendorfer, Claudia Haferlach, Andreas Trumpp, Wolf-Karsten Hofmann, Hind Medyouf, and Daniel Nowak |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1586649639 | ||
| 003 | DE-627 | ||
| 005 | 20230427034218.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 190128s2016 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/blood-2015-11-679167 |2 doi | |
| 035 | |a (DE-627)1586649639 | ||
| 035 | |a (DE-576)516649639 | ||
| 035 | |a (DE-599)BSZ516649639 | ||
| 035 | |a (OCoLC)1341034569 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Mossner, Maximilian |d 1984- |e VerfasserIn |0 (DE-588)1033912379 |0 (DE-627)745111572 |0 (DE-576)381596222 |4 aut | |
| 245 | 1 | 0 | |a Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure |c Maximilian Mossner, Johann-Christoph Jann, Janina Wittig, Florian Nolte, Stephanie Fey, Verena Nowak, Julia Obländer, Jovita Pressler, Iris Palme, Christina Xanthopoulos, Tobias Boch, Georgia Metzgeroth, Henning Röhl, Stephanie H. Witt, Helene Dukal, Corinna Klein, Steffen Schmitt, Patrick Gelß, Uwe Platzbecker, Ekaterina Balaian, Alice Fabarius, Helmut Blum, Torsten J. Schulze, Manja Meggendorfer, Claudia Haferlach, Andreas Trumpp, Wolf-Karsten Hofmann, Hind Medyouf, and Daniel Nowak |
| 264 | 1 | |c June 6, 2016 | |
| 300 | |a 14 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 28.01.2019 | ||
| 520 | |a Clonal evolution is believed to be a main driver for progression of various types of cancer and implicated in facilitating resistance to drugs. However, the hierarchical organization of malignant clones in the hematopoiesis of myelodysplastic syndromes (MDS) and its impact on response to drug therapy remain poorly understood. Using high-throughput sequencing of patient and xenografted cells, we evaluated the intratumoral heterogeneity (n= 54) and reconstructed mutational trajectories (n = 39) in patients suffering from MDS (n = 52) and chronic myelomonocytic leukemia-1 (n = 2). We identified linear and also branching evolution paths and confirmed on a patient-specific level that somatic mutations in epigenetic regulators and RNA splicing genes frequently constitute isolated disease-initiating events. Using high-throughput exome- and/or deep-sequencing, we analyzed 103 chronologically acquired samples from 22 patients covering a cumulative observation time of 75 years MDS disease progression. Our data revealed highly dynamic shaping of complex oligoclonal architectures, specifically upon treatment with lenalidomide and other drugs. Despite initial clinical response to treatment, patients’ marrow persistently remained clonal with rapid outgrowth of founder-, sub-, or even fully independent clones, indicating an increased dynamic rate of clonal turnover. The emergence and disappearance of specific clones frequently correlated with changes of clinical parameters, highlighting their distinct and far-reaching functional properties. Intriguingly, increasingly complex mutational trajectories are frequently accompanied by clinical progression during the course of disease. These data substantiate a need for regular broad molecular monitoring to guide clinical treatment decisions in MDS. | ||
| 700 | 1 | |a Jann, Johann-Christoph |d 1989- |e VerfasserIn |0 (DE-588)1069891827 |0 (DE-627)822939851 |0 (DE-576)429585837 |4 aut | |
| 700 | 1 | |a Wittig, Janina |d 1992- |e VerfasserIn |0 (DE-588)1176461931 |0 (DE-627)1047463865 |0 (DE-576)51664940X |4 aut | |
| 700 | 1 | |a Nolte, Florian |d 1976- |e VerfasserIn |0 (DE-588)1033390348 |0 (DE-627)741150433 |0 (DE-576)380987031 |4 aut | |
| 700 | 1 | |a Fey, Stephanie |d 1989- |e VerfasserIn |0 (DE-588)1163570567 |0 (DE-627)1027889271 |0 (DE-576)508057922 |4 aut | |
| 700 | 1 | |a Nowak, Verena |d 1981- |e VerfasserIn |0 (DE-588)1033389986 |0 (DE-627)741149680 |0 (DE-576)380986175 |4 aut | |
| 700 | 1 | |a Obländer, Julia |d 1984- |e VerfasserIn |0 (DE-588)1033921459 |0 (DE-627)743670752 |0 (DE-576)381601609 |4 aut | |
| 700 | 1 | |a Pressler, Jovita |d 1993- |e VerfasserIn |0 (DE-588)1163570788 |0 (DE-627)1027889700 |0 (DE-576)508058201 |4 aut | |
| 700 | 1 | |a Palme, Iris |d 1969- |e VerfasserIn |0 (DE-588)1163571024 |0 (DE-627)1027890113 |0 (DE-576)508058570 |4 aut | |
| 700 | 1 | |a Xanthopoulos, Christina |d 1992- |e VerfasserIn |0 (DE-588)1163571210 |0 (DE-627)1027890547 |0 (DE-576)508058937 |4 aut | |
| 700 | 1 | |a Boch, Tobias |d 1984- |e VerfasserIn |0 (DE-588)1052922015 |0 (DE-627)789313847 |0 (DE-576)40866732X |4 aut | |
| 700 | 1 | |a Metzgeroth, Georgia |d 1972- |e VerfasserIn |0 (DE-588)1051897661 |0 (DE-627)786986832 |0 (DE-576)407534075 |4 aut | |
| 700 | 1 | |a Röhl, Henning |d 1976- |e VerfasserIn |0 (DE-588)1023974940 |0 (DE-627)718992075 |0 (DE-576)367747456 |4 aut | |
| 700 | 1 | |a Witt, Stephanie |d 1970- |e VerfasserIn |0 (DE-588)132177897 |0 (DE-627)519022432 |0 (DE-576)298988399 |4 aut | |
| 700 | 1 | |a Fabarius, Alice |d 1965- |e VerfasserIn |0 (DE-588)1037001281 |0 (DE-627)751728314 |0 (DE-576)390896667 |4 aut | |
| 700 | 1 | |a Schulze, Torsten |d 1975- |e VerfasserIn |0 (DE-588)133926524 |0 (DE-627)558736629 |0 (DE-576)300197187 |4 aut | |
| 700 | 1 | |a Hofmann, Wolf-Karsten |d 1967- |e VerfasserIn |0 (DE-588)114154635 |0 (DE-627)691208751 |0 (DE-576)351568336 |4 aut | |
| 700 | 1 | |a Nowak, Daniel |d 1976- |e VerfasserIn |0 (DE-588)131932063 |0 (DE-627)51618041X |0 (DE-576)298844540 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood |d Washington, DC : American Society of Hematology, 1946 |g 128(2016), 9, Seite 1246-1259 |h Online-Ressource |w (DE-627)266886647 |w (DE-600)1468538-3 |w (DE-576)075961938 |x 1528-0020 |7 nnas |a Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure |
| 773 | 1 | 8 | |g volume:128 |g year:2016 |g number:9 |g pages:1246-1259 |g extent:14 |a Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/blood-2015-11-679167 |x Verlag |x Resolving-System |3 Volltext |
| 856 | 4 | 0 | |u http://www.bloodjournal.org.ezproxy.medma.uni-heidelberg.de/content/128/9/1246 |x Verlag |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20190128 | ||
| 992 | |a 20190128 | ||
| 993 | |a Article | ||
| 993 | |a Article | ||
| 994 | |a 2016 | ||
| 994 | |a 2016 | ||
| 998 | |g 131932063 |a Nowak, Daniel |m 131932063:Nowak, Daniel |d 60000 |d 61200 |e 60000PN131932063 |e 61200PN131932063 |k 0/60000/ |k 1/60000/61200/ |p 29 |y j | ||
| 998 | |g 114154635 |a Hofmann, Wolf-Karsten |m 114154635:Hofmann, Wolf-Karsten |d 60000 |d 61200 |e 60000PH114154635 |e 61200PH114154635 |k 0/60000/ |k 1/60000/61200/ |p 27 | ||
| 998 | |g 133926524 |a Schulze, Torsten |m 133926524:Schulze, Torsten |d 60000 |d 63500 |e 60000PS133926524 |e 63500PS133926524 |k 0/60000/ |k 1/60000/63500/ |p 23 | ||
| 998 | |g 1037001281 |a Fabarius, Alice |m 1037001281:Fabarius, Alice |d 60000 |e 60000PF1037001281 |k 0/60000/ |p 15 | ||
| 998 | |g 132177897 |a Witt, Stephanie |m 132177897:Witt, Stephanie |d 60000 |e 60000PW132177897 |k 0/60000/ |p 14 | ||
| 998 | |g 1023974940 |a Röhl, Henning |m 1023974940:Röhl, Henning |d 60000 |d 62400 |e 60000PR1023974940 |e 62400PR1023974940 |k 0/60000/ |k 1/60000/62400/ |p 13 | ||
| 998 | |g 1051897661 |a Metzgeroth, Georgia |m 1051897661:Metzgeroth, Georgia |d 60000 |d 61200 |e 60000PM1051897661 |e 61200PM1051897661 |k 0/60000/ |k 1/60000/61200/ |p 12 | ||
| 998 | |g 1052922015 |a Boch, Tobias |m 1052922015:Boch, Tobias |d 60000 |d 61200 |e 60000PB1052922015 |e 61200PB1052922015 |k 0/60000/ |k 1/60000/61200/ |p 11 | ||
| 998 | |g 1163571210 |a Xanthopoulos, Christina |m 1163571210:Xanthopoulos, Christina |d 60000 |d 61200 |e 60000PX1163571210 |e 61200PX1163571210 |k 0/60000/ |k 1/60000/61200/ |p 10 | ||
| 998 | |g 1163571024 |a Palme, Iris |m 1163571024:Palme, Iris |d 60000 |d 61200 |e 60000PP1163571024 |e 61200PP1163571024 |k 0/60000/ |k 1/60000/61200/ |p 9 | ||
| 998 | |g 1163570788 |a Pressler, Jovita |m 1163570788:Pressler, Jovita |d 60000 |d 61200 |e 60000PP1163570788 |e 61200PP1163570788 |k 0/60000/ |k 1/60000/61200/ |p 8 | ||
| 998 | |g 1033921459 |a Obländer, Julia |m 1033921459:Obländer, Julia |d 60000 |d 61200 |e 60000PO1033921459 |e 61200PO1033921459 |k 0/60000/ |k 1/60000/61200/ |p 7 | ||
| 998 | |g 1033389986 |a Nowak, Verena |m 1033389986:Nowak, Verena |d 60000 |d 61200 |e 60000PN1033389986 |e 61200PN1033389986 |k 0/60000/ |k 1/60000/61200/ |p 6 | ||
| 998 | |g 1163570567 |a Fey, Stephanie |m 1163570567:Fey, Stephanie |d 60000 |d 61200 |e 60000PF1163570567 |e 61200PF1163570567 |k 0/60000/ |k 1/60000/61200/ |p 5 | ||
| 998 | |g 1033390348 |a Nolte, Florian |m 1033390348:Nolte, Florian |d 60000 |d 61200 |e 60000PN1033390348 |e 61200PN1033390348 |k 0/60000/ |k 1/60000/61200/ |p 4 | ||
| 998 | |g 1176461931 |a Wittig, Janina |m 1176461931:Wittig, Janina |d 60000 |d 61200 |e 60000PW1176461931 |e 61200PW1176461931 |k 0/60000/ |k 1/60000/61200/ |p 3 | ||
| 998 | |g 1069891827 |a Jann, Johann-Christoph |m 1069891827:Jann, Johann-Christoph |d 60000 |d 61200 |e 60000PJ1069891827 |e 61200PJ1069891827 |k 0/60000/ |k 1/60000/61200/ |p 2 | ||
| 998 | |g 1033912379 |a Mossner, Maximilian |m 1033912379:Mossner, Maximilian |d 60000 |d 61200 |e 60000PM1033912379 |e 61200PM1033912379 |k 0/60000/ |k 1/60000/61200/ |p 1 |x j | ||
| 999 | |a KXP-PPN1586649639 |e 3049343214 | ||
| 999 | |a KXP-PPN1586649639 |e 3049340843 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"title":[{"title_sort":"Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure","title":"Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure"}],"person":[{"given":"Maximilian","display":"Mossner, Maximilian","role":"aut","family":"Mossner","roleDisplay":"VerfasserIn"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Jann","given":"Johann-Christoph","display":"Jann, Johann-Christoph"},{"given":"Janina","display":"Wittig, Janina","role":"aut","family":"Wittig","roleDisplay":"VerfasserIn"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Nolte","given":"Florian","display":"Nolte, Florian"},{"display":"Fey, Stephanie","given":"Stephanie","family":"Fey","roleDisplay":"VerfasserIn","role":"aut"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Nowak","given":"Verena","display":"Nowak, Verena"},{"given":"Julia","display":"Obländer, Julia","role":"aut","roleDisplay":"VerfasserIn","family":"Obländer"},{"display":"Pressler, Jovita","given":"Jovita","family":"Pressler","roleDisplay":"VerfasserIn","role":"aut"},{"given":"Iris","display":"Palme, Iris","role":"aut","roleDisplay":"VerfasserIn","family":"Palme"},{"given":"Christina","display":"Xanthopoulos, Christina","role":"aut","roleDisplay":"VerfasserIn","family":"Xanthopoulos"},{"given":"Tobias","display":"Boch, Tobias","role":"aut","family":"Boch","roleDisplay":"VerfasserIn"},{"roleDisplay":"VerfasserIn","family":"Metzgeroth","role":"aut","display":"Metzgeroth, Georgia","given":"Georgia"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Röhl","given":"Henning","display":"Röhl, Henning"},{"display":"Witt, Stephanie","given":"Stephanie","roleDisplay":"VerfasserIn","family":"Witt","role":"aut"},{"role":"aut","roleDisplay":"VerfasserIn","family":"Fabarius","given":"Alice","display":"Fabarius, Alice"},{"role":"aut","family":"Schulze","roleDisplay":"VerfasserIn","given":"Torsten","display":"Schulze, Torsten"},{"family":"Hofmann","roleDisplay":"VerfasserIn","role":"aut","display":"Hofmann, Wolf-Karsten","given":"Wolf-Karsten"},{"family":"Nowak","roleDisplay":"VerfasserIn","role":"aut","display":"Nowak, Daniel","given":"Daniel"}],"recId":"1586649639","relHost":[{"corporate":[{"display":"American Society of Hematology","role":"isb","roleDisplay":"Herausgebendes Organ"}],"language":["eng"],"title":[{"title_sort":"Blood","subtitle":"journal of the American Society of Hematology","title":"Blood"}],"disp":"Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failureBlood","part":{"text":"128(2016), 9, Seite 1246-1259","pages":"1246-1259","volume":"128","extent":"14","issue":"9","year":"2016"},"recId":"266886647","origin":[{"dateIssuedKey":"1946","publisher":"American Society of Hematology ; Saunders ; HighWire Press","publisherPlace":"Washington, DC ; Philadelphia, Pa. ; Stanford, Calif.","dateIssuedDisp":"1946-"}],"type":{"bibl":"periodical","media":"Online-Ressource"},"note":["Gesehen am 21.04.2023"],"physDesc":[{"extent":"Online-Ressource"}],"titleAlt":[{"title":"Blood online"}],"id":{"eki":["266886647"],"issn":["1528-0020"],"zdb":["1468538-3"]},"pubHistory":["1.1946 -"]}],"language":["eng"],"id":{"doi":["10.1182/blood-2015-11-679167"],"eki":["1586649639"]},"name":{"displayForm":["Maximilian Mossner, Johann-Christoph Jann, Janina Wittig, Florian Nolte, Stephanie Fey, Verena Nowak, Julia Obländer, Jovita Pressler, Iris Palme, Christina Xanthopoulos, Tobias Boch, Georgia Metzgeroth, Henning Röhl, Stephanie H. Witt, Helene Dukal, Corinna Klein, Steffen Schmitt, Patrick Gelß, Uwe Platzbecker, Ekaterina Balaian, Alice Fabarius, Helmut Blum, Torsten J. Schulze, Manja Meggendorfer, Claudia Haferlach, Andreas Trumpp, Wolf-Karsten Hofmann, Hind Medyouf, and Daniel Nowak"]},"origin":[{"dateIssuedDisp":"June 6, 2016","dateIssuedKey":"2016"}],"type":{"bibl":"article-journal","media":"Online-Ressource"},"note":["Gesehen am 28.01.2019"],"physDesc":[{"extent":"14 S."}]} | ||
| SRT | |a MOSSNERMAXMUTATIONAL6201 | ||