Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

Peggy Kirstetter; Mikkel B Schuster; Oksana Bereshchenko; Susan Moore; Heidi Dvinge; Elke Kurz; Kim Theilgaard-Mönch; Robert Månsson; Thomas A Pedersen; Thomas Pabst; Evelin Schrock; Bo T Porse; Sten Eirik W Jacobsen; Paul Bertone; Daniel G Tenen; Claus Nerlov

doi:10.1016/j.ccr.2008.02.008

Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

Peggy Kirstetter, Mikkel B Schuster, Oksana Bereshchenko, Susan Moore, Heidi Dvinge, Elke Kurz, Kim Theilgaard-Mönch, Robert Månsson, Thomas A Pedersen, Thomas Pabst, Evelin Schrock, Bo T Porse, Sten Eirik W Jacobsen, Paul Bertone, Daniel G Tenen, Claus Nerlov

217 Citations (Scopus)

Abstract

Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.

Original language	English
Journal	Cancer Cell
Volume	13
Issue number	4
Pages (from-to)	299-310
Number of pages	12
ISSN	1535-6108
DOIs	https://doi.org/10.1016/j.ccr.2008.02.008
Publication status	Published - Apr 2008
Externally published	Yes

Keywords

Animals
CCAAT-Enhancer-Binding Protein-alpha/deficiency
Cell Differentiation
Disease Progression
Gene Expression Profiling
Gene Expression Regulation, Leukemic
Granulocytes/cytology
Leukemia, Myelomonocytic, Acute/genetics
Macrophage-1 Antigen/metabolism
Mice
Mice, Knockout
Models, Biological
Mutant Proteins/metabolism
Myeloid Progenitor Cells/pathology
Neoplasm Transplantation
Neoplastic Stem Cells/metabolism
Phenotype
Protein Isoforms/metabolism
Proto-Oncogene Proteins c-kit/metabolism

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Kirstetter, P., Schuster, M. B., Bereshchenko, O., Moore, S., Dvinge, H., Kurz, E., Theilgaard-Mönch, K., Månsson, R., Pedersen, T. A., Pabst, T., Schrock, E., Porse, B. T., Jacobsen, S. E. W., Bertone, P., Tenen, D. G., & Nerlov, C. (2008). Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell, 13(4), 299-310. https://doi.org/10.1016/j.ccr.2008.02.008

Kirstetter, P, Schuster, MB, Bereshchenko, O, Moore, S, Dvinge, H, Kurz, E, Theilgaard-Mönch, K, Månsson, R, Pedersen, TA, Pabst, T, Schrock, E, Porse, BT, Jacobsen, SEW, Bertone, P, Tenen, DG & Nerlov, C 2008, 'Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells', Cancer Cell, vol. 13, no. 4, pp. 299-310. https://doi.org/10.1016/j.ccr.2008.02.008

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title = "Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells",

abstract = "Mutations in the CEBPA gene are present in 7\%-10\% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.",

keywords = "Animals, CCAAT-Enhancer-Binding Protein-alpha/deficiency, Cell Differentiation, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Granulocytes/cytology, Leukemia, Myelomonocytic, Acute/genetics, Macrophage-1 Antigen/metabolism, Mice, Mice, Knockout, Models, Biological, Mutant Proteins/metabolism, Myeloid Progenitor Cells/pathology, Neoplasm Transplantation, Neoplastic Stem Cells/metabolism, Phenotype, Protein Isoforms/metabolism, Proto-Oncogene Proteins c-kit/metabolism",

author = "Peggy Kirstetter and Schuster, \{Mikkel B\} and Oksana Bereshchenko and Susan Moore and Heidi Dvinge and Elke Kurz and Kim Theilgaard-M{\"o}nch and Robert M{\aa}nsson and Pedersen, \{Thomas A\} and Thomas Pabst and Evelin Schrock and Porse, \{Bo T\} and Jacobsen, \{Sten Eirik W\} and Paul Bertone and Tenen, \{Daniel G\} and Claus Nerlov",

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T1 - Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

AU - Kirstetter, Peggy

AU - Schuster, Mikkel B

AU - Bereshchenko, Oksana

AU - Moore, Susan

AU - Dvinge, Heidi

AU - Kurz, Elke

AU - Theilgaard-Mönch, Kim

AU - Månsson, Robert

AU - Pedersen, Thomas A

AU - Pabst, Thomas

AU - Schrock, Evelin

AU - Porse, Bo T

AU - Jacobsen, Sten Eirik W

AU - Bertone, Paul

AU - Tenen, Daniel G

AU - Nerlov, Claus

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N2 - Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.

AB - Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.

KW - Animals

KW - CCAAT-Enhancer-Binding Protein-alpha/deficiency

KW - Cell Differentiation

KW - Disease Progression

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Leukemic

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KW - Leukemia, Myelomonocytic, Acute/genetics

KW - Macrophage-1 Antigen/metabolism

KW - Mice

KW - Mice, Knockout

KW - Models, Biological

KW - Mutant Proteins/metabolism

KW - Myeloid Progenitor Cells/pathology

KW - Neoplasm Transplantation

KW - Neoplastic Stem Cells/metabolism

KW - Phenotype

KW - Protein Isoforms/metabolism

KW - Proto-Oncogene Proteins c-kit/metabolism

UR - https://www.scopus.com/pages/publications/41249103144

U2 - 10.1016/j.ccr.2008.02.008

DO - 10.1016/j.ccr.2008.02.008

M3 - Journal article

C2 - 18394553

SN - 1535-6108

VL - 13

SP - 299

EP - 310

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

Abstract

Keywords

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