Lack of the p42 form of C/EBPα leads to spontaneous immortalization and lineage infidelity of committed myeloid progenitors

TY - JOUR

T1 - Lack of the p42 form of C/EBPα leads to spontaneous immortalization and lineage infidelity of committed myeloid progenitors

AU - Schuster, Mikkel B

AU - Frank, Anne-Katrine

AU - Bagger, Frederik O

AU - Rapin, Nicolas

AU - Vikesaa, Jonas

AU - Porse, Bo T

N1 - Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

PY - 2013/10

Y1 - 2013/10

N2 - Acute myeloid leukemia (AML) develops via a multistep process involving several genetic and epigenetic events, which ultimately leads to the formation of a heterogeneous population of malignant cells, of which only a small subpopulation termed the leukemia initiating cell (LIC) is able to sustain the leukemia. The identity of the LIC is highly diverse and ranges from populations resembling hematopoietic stem cells or multipotent progenitors (MPPs) to more committed myeloid progenitors, and the question still remains whether this is a direct consequence of which cells are targets of the final transforming events. In this study, we use premalignant cells from a Cebpa mutant AML model, in which the LIC population resembles granulocyte-macrophage progenitors (GMPs), to show that premalignant GMPs undergo spontaneous immortalization with a high clonal frequency when cultured in vitro, suggesting that these cells constitute the target of the final transforming events. Furthermore, we show that premalignant GMPs are characterized by a distinct T cell gene expression signature correlating with an increased potential for differentiation toward the T cell lineage. These findings have implications for our understanding of the transcriptional wiring in premalignant myeloid progenitors and how this contributes to the development of AML.

AB - Acute myeloid leukemia (AML) develops via a multistep process involving several genetic and epigenetic events, which ultimately leads to the formation of a heterogeneous population of malignant cells, of which only a small subpopulation termed the leukemia initiating cell (LIC) is able to sustain the leukemia. The identity of the LIC is highly diverse and ranges from populations resembling hematopoietic stem cells or multipotent progenitors (MPPs) to more committed myeloid progenitors, and the question still remains whether this is a direct consequence of which cells are targets of the final transforming events. In this study, we use premalignant cells from a Cebpa mutant AML model, in which the LIC population resembles granulocyte-macrophage progenitors (GMPs), to show that premalignant GMPs undergo spontaneous immortalization with a high clonal frequency when cultured in vitro, suggesting that these cells constitute the target of the final transforming events. Furthermore, we show that premalignant GMPs are characterized by a distinct T cell gene expression signature correlating with an increased potential for differentiation toward the T cell lineage. These findings have implications for our understanding of the transcriptional wiring in premalignant myeloid progenitors and how this contributes to the development of AML.

KW - Animals

KW - CCAAT-Enhancer-Binding Protein-alpha

KW - Cell Differentiation

KW - Cell Lineage

KW - Cell Proliferation

KW - Cells, Cultured

KW - Gene Expression Regulation

KW - Genetic Variation

KW - Leukemia, Myeloid, Acute

KW - Mice

KW - Mutation

KW - Myeloid Progenitor Cells

KW - Phenotype

KW - Time Factors

U2 - 10.1016/j.exphem.2013.06.003

DO - 10.1016/j.exphem.2013.06.003

M3 - Journal article

C2 - 23831605

SN - 0301-472X

VL - 41

SP - 882

EP - 893

JO - Experimental Hematology

JF - Experimental Hematology

IS - 10

ER -