The clinical mutatome of core binding factor leukemia
The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
|---|---|
| Enthalten in: |
Leukemia - 34(2020), 6 vom: 02. Juni, Seite 1553-1562 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Themen: |
Core Binding Factors |
|---|
| Anmerkungen: |
Date Completed 07.10.2020 Date Revised 22.01.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41375-019-0697-0 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM304964689 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM304964689 | ||
| 003 | DE-627 | ||
| 005 | 20231225120126.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41375-019-0697-0 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1016.xml |
| 035 | |a (DE-627)NLM304964689 | ||
| 035 | |a (NLM)31896782 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Opatz, Sabrina |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The clinical mutatome of core binding factor leukemia |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.10.2020 | ||
| 500 | |a Date Revised 22.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Core Binding Factors |2 NLM | |
| 700 | 1 | |a Bamopoulos, Stefanos A |e verfasserin |4 aut | |
| 700 | 1 | |a Metzeler, Klaus H |e verfasserin |4 aut | |
| 700 | 1 | |a Herold, Tobias |e verfasserin |4 aut | |
| 700 | 1 | |a Ksienzyk, Bianka |e verfasserin |4 aut | |
| 700 | 1 | |a Bräundl, Kathrin |e verfasserin |4 aut | |
| 700 | 1 | |a Tschuri, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Vosberg, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Konstandin, Nikola P |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Hartmann, Luise |e verfasserin |4 aut | |
| 700 | 1 | |a Graf, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Krebs, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Blum, Helmut |e verfasserin |4 aut | |
| 700 | 1 | |a Schneider, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Thiede, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Middeke, Jan Moritz |e verfasserin |4 aut | |
| 700 | 1 | |a Stölzel, Friedrich |e verfasserin |4 aut | |
| 700 | 1 | |a Röllig, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Schetelig, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Ehninger, Gerhard |e verfasserin |4 aut | |
| 700 | 1 | |a Krämer, Alwin |e verfasserin |4 aut | |
| 700 | 1 | |a Braess, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Görlich, Dennis |e verfasserin |4 aut | |
| 700 | 1 | |a Sauerland, Maria Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Berdel, Wolfgang E |e verfasserin |4 aut | |
| 700 | 1 | |a Wörmann, Bernhard J |e verfasserin |4 aut | |
| 700 | 1 | |a Hiddemann, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Spiekermann, Karsten |e verfasserin |4 aut | |
| 700 | 1 | |a Bohlander, Stefan K |e verfasserin |4 aut | |
| 700 | 1 | |a Greif, Philipp A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Leukemia |d 1989 |g 34(2020), 6 vom: 02. Juni, Seite 1553-1562 |w (DE-627)NLM012593788 |x 1476-5551 |7 nnns |
| 773 | 1 | 8 | |g volume:34 |g year:2020 |g number:6 |g day:02 |g month:06 |g pages:1553-1562 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41375-019-0697-0 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 34 |j 2020 |e 6 |b 02 |c 06 |h 1553-1562 | ||