CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome

Franziska Taube; Julia Annabell Georgi; the Study Alliance Leukemia (SAL); Michael Kramer; Sebastian Stasik; Jan Moritz Middeke; Christoph Röllig; Utz Krug; Alwin Krämer; Sebastian Scholl; Andreas Hochhaus; Tim H. Brümmendorf; Ralph Naumann; Andreas Petzold; Roger Mulet-Lazaro; Peter J.M. Valk; Björn Steffen; Hermann Einsele; Markus Schaich; Andreas Burchert; Andreas Neubauer; Kerstin Schäfer-Eckart; Christoph Schliemann; Stefan W. Krause; Mathias Hänel; Richard Noppeney; Ulrich Kaiser; Claudia D. Baldus; Martin Kaufmann; Sylvia Herold; Friedrich Stölzel; Katja Sockel; Malte von Bonin; Carsten Müller-Tidow; Uwe Platzbecker; Wolfgang E. Berdel; Hubert Serve; Gerhard Ehninger; Martin Bornhäuser; Johannes Schetelig; Christian Thiede

doi:10.1182/blood.2020009680

CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome

Franziska Taube, Julia Annabell Georgi, the Study Alliance Leukemia (SAL), Michael Kramer, Sebastian Stasik, Jan Moritz Middeke, Christoph Röllig, Utz Krug, Alwin Krämer, Sebastian Scholl, Andreas Hochhaus, Tim H. Brümmendorf, Ralph Naumann, Andreas Petzold, Roger Mulet-Lazaro, Peter J.M. Valk, Björn Steffen, Hermann Einsele, Markus Schaich, Andreas BurchertAndreas Neubauer, Kerstin Schäfer-Eckart, Christoph Schliemann, Stefan W. Krause, Mathias Hänel, Richard Noppeney, Ulrich Kaiser, Claudia D. Baldus, Martin Kaufmann, Sylvia Herold, Friedrich Stölzel, Katja Sockel, Malte von Bonin, Carsten Müller-Tidow, Uwe Platzbecker, Wolfgang E. Berdel, Hubert Serve, Gerhard Ehninger, Martin Bornhäuser, Johannes Schetelig, Christian Thiede^*

^*Corresponding author for this work

Hematology

Research output: Contribution to journal › Article › Academic › peer-review

107 Citations (Scopus)

Abstract

Biallelic mutations of the CEBPA gene (CEBPA^bi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPA^sm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPA^sm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPA^bi and 109 CEBPA^sm (60 affecting the N-terminal transactivation domains [CEBPA^smTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPA^smbZIP]). Interestingly, patients carrying CEBPA^bi or CEBPA^smbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 10⁹/L and 35.7 × 10⁹/L) than patients with CEBPA^smTAD (median age, 63 years, median WBC 13.1 × 10⁹/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPA^bi; 36.7% CEBPA^smbZIP vs 6.7% CEBPA^smTAD; P < .001) or NPM1 mutations (3.1% CEBPA^bi; 8.2% CEBPA^smbZIP vs 38.3% CEBPA^smTAD; P < .001). CEBPA^bi and CEBPA^smbZIP, but not CEBPA^smTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPA^bZIP-inf). When patients were classified according to CEBPA^bZIP-inf and CEBPA^other (including CEBPA^smTAD and non-CEBPA^bZIP-inf), only patients bearing CEBPA^bZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

Original language	English
Pages (from-to)	87-103
Number of pages	17
Journal	Blood
Volume	139
Issue number	1
DOIs	https://doi.org/10.1182/blood.2020009680
Publication status	Published - 6 Jan 2022

Bibliographical note

Funding Information: This study was supported in part by grants from the Federal Ministry of Education and Research 01GS0872 (C.T.).

Publisher Copyright: © 2022 American Society of Hematology

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10.1182/blood.2020009680

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Taube, F., Georgi, J. A., the Study Alliance Leukemia (SAL), Kramer, M., Stasik, S., Middeke, J. M., Röllig, C., Krug, U., Krämer, A., Scholl, S., Hochhaus, A., Brümmendorf, T. H., Naumann, R., Petzold, A., Mulet-Lazaro, R., Valk, P. J. M., Steffen, B., Einsele, H., Schaich, M., ... Thiede, C. (2022). CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome. Blood, 139(1), 87-103. https://doi.org/10.1182/blood.2020009680

@article{333059fd2f0840d0b3a3da5ce984e6e0,

title = "CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome",

abstract = "Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.",

author = "Franziska Taube and Georgi, {Julia Annabell} and {the Study Alliance Leukemia (SAL)} and Michael Kramer and Sebastian Stasik and Middeke, {Jan Moritz} and Christoph R{\"o}llig and Utz Krug and Alwin Kr{\"a}mer and Sebastian Scholl and Andreas Hochhaus and Br{\"u}mmendorf, {Tim H.} and Ralph Naumann and Andreas Petzold and Roger Mulet-Lazaro and Valk, {Peter J.M.} and Bj{\"o}rn Steffen and Hermann Einsele and Markus Schaich and Andreas Burchert and Andreas Neubauer and Kerstin Sch{\"a}fer-Eckart and Christoph Schliemann and Krause, {Stefan W.} and Mathias H{\"a}nel and Richard Noppeney and Ulrich Kaiser and Baldus, {Claudia D.} and Martin Kaufmann and Sylvia Herold and Friedrich St{\"o}lzel and Katja Sockel and {von Bonin}, Malte and Carsten M{\"u}ller-Tidow and Uwe Platzbecker and Berdel, {Wolfgang E.} and Hubert Serve and Gerhard Ehninger and Martin Bornh{\"a}user and Johannes Schetelig and Christian Thiede",

note = "Funding Information: This study was supported in part by grants from the Federal Ministry of Education and Research 01GS0872 (C.T.). Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",

year = "2022",

month = jan,

day = "6",

doi = "10.1182/blood.2020009680",

language = "English",

volume = "139",

pages = "87--103",

journal = "Blood",

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publisher = "Elsevier",

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Taube, F, Georgi, JA, the Study Alliance Leukemia (SAL), Kramer, M, Stasik, S, Middeke, JM, Röllig, C, Krug, U, Krämer, A, Scholl, S, Hochhaus, A, Brümmendorf, TH, Naumann, R, Petzold, A, Mulet-Lazaro, R , Valk, PJM, Steffen, B, Einsele, H, Schaich, M, Burchert, A, Neubauer, A, Schäfer-Eckart, K, Schliemann, C, Krause, SW, Hänel, M, Noppeney, R, Kaiser, U, Baldus, CD, Kaufmann, M, Herold, S, Stölzel, F, Sockel, K, von Bonin, M, Müller-Tidow, C, Platzbecker, U, Berdel, WE, Serve, H, Ehninger, G, Bornhäuser, M, Schetelig, J & Thiede, C 2022, 'CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome', Blood, vol. 139, no. 1, pp. 87-103. https://doi.org/10.1182/blood.2020009680

TY - JOUR

T1 - CEBPA mutations in 4708 patients with acute myeloid leukemia

T2 - differential impact of bZIP and TAD mutations on outcome

AU - Taube, Franziska

AU - Georgi, Julia Annabell

AU - the Study Alliance Leukemia (SAL)

AU - Kramer, Michael

AU - Stasik, Sebastian

AU - Middeke, Jan Moritz

AU - Röllig, Christoph

AU - Krug, Utz

AU - Krämer, Alwin

AU - Scholl, Sebastian

AU - Hochhaus, Andreas

AU - Brümmendorf, Tim H.

AU - Naumann, Ralph

AU - Petzold, Andreas

AU - Mulet-Lazaro, Roger

AU - Valk, Peter J.M.

AU - Steffen, Björn

AU - Einsele, Hermann

AU - Schaich, Markus

AU - Burchert, Andreas

AU - Neubauer, Andreas

AU - Schäfer-Eckart, Kerstin

AU - Schliemann, Christoph

AU - Krause, Stefan W.

AU - Hänel, Mathias

AU - Noppeney, Richard

AU - Kaiser, Ulrich

AU - Baldus, Claudia D.

AU - Kaufmann, Martin

AU - Herold, Sylvia

AU - Stölzel, Friedrich

AU - Sockel, Katja

AU - von Bonin, Malte

AU - Müller-Tidow, Carsten

AU - Platzbecker, Uwe

AU - Berdel, Wolfgang E.

AU - Serve, Hubert

AU - Ehninger, Gerhard

AU - Bornhäuser, Martin

AU - Schetelig, Johannes

AU - Thiede, Christian

PY - 2022/1/6

Y1 - 2022/1/6

N2 - Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

AB - Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

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U2 - 10.1182/blood.2020009680

DO - 10.1182/blood.2020009680

M3 - Article

C2 - 34320176

AN - SCOPUS:85122257189

SN - 0006-4971

VL - 139

SP - 87

EP - 103

JO - Blood

JF - Blood

IS - 1

ER -

CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome

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