Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBPα

Fukuchi, Yumi; Shibata, Fumi; Ito, Miyuki; Goto‐Koshino, Yuko; Sotomaru, Yusuke; Ito, Mamoru; Kitamura, Toshio; Nakajima, Hitoshi

doi:10.1038/sj.emboj.7601199

Cited by 50 publications

(50 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These observations mirror those from previous studies that showed that CEBPA has lineage switch potential when expressed in lymphoid cells. [43][44][45][46][47] Although the role of C/EBP␣ in lymphoid cell fate decision may not be fully understood yet, as highlighted by recent observations indicating that overexpression of C/EBP␣ due to chromosomal translocations may be involved in B-cell ALLs, 48,49 our studies show that decreased expression of C/EBP␣ in hematopoietic stem cells can be sufficient to induce T-cell transcripts.…”

Section: Discussionmentioning

confidence: 85%

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1

Wouters

Jordà²,

Keeshan

et al. 2007

Blood

173

182

View full text Add to dashboard Cite

Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of Tcell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML. IntroductionAcute myeloid leukemia (AML) is a heterogeneous disease with respect to its underlying genetic abnormalities and clinical biology. 1 It has therefore been postulated that AML, although always characterized by a malignant accumulation of myeloid progenitor cells, in fact represents not a single disease, but a group of neoplasms. Cytogenetic and molecular analyses, studying specific chromosomal translocations and mutations, are used to identify subgroups of AML with distinct biologic and clinical behavior. Recent developments in microarray research have resulted in further improvements in the characterization of the molecular heterogeneity of AML, 2 and gene expression profiling (GEP) studies have demonstrated that specific chromosomal aberrations, such as the common translocations t(8;21), t(15;17), and inv(16), correlate with unique expression signatures. [3][4][5] In a GEP study of 285 cases of de novo AML, we found that specific expression profiles are associated with other recurrent genetic aberrations such as mutations in NPM1 and alterations involving MLL, and with overexpression of the proto-oncogene EVI1 as well. 4,6 Some AMLs lacking these particular abnormalities were found to express the same characteristic profiles, suggesting that deregulation of the same pathways had occurred through yet-unknown mechanisms. This study also showed that 2 distinct expression clusters (no. 4 and no. 15) consisted primarily of AML cases with mutations in CEBPA, the gene encoding the basic leucine zipper transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣). C/EBP␣ is a critical regulator of hematopoietic stem cell (HSC) homeostasis and myeloid differentiation, [7][8][9][10] and multiple studies have shown that C/EBP␣ function is frequently ...

show abstract

Section: Discussionmentioning

confidence: 85%

Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1

Wouters

Jordà²,

Keeshan

et al. 2007

Blood

173

182

View full text Add to dashboard Cite

show abstract

“…[53][54][55] Indeed, recent work has shown that ectopic C/EBP␣ expression can actually direct differentiation along the monocytic and not the predicted granulocytic lineage. [55][56][57][58] To resolve this conundrum, a recent study has demonstrated the importance of "secondary" cell-fate determinants, which are regulated by the primary determinant and act as counterantagonistic repressors; thus, secondary determinants such as Gfi1 and Egr1/Egr2 may be pivotal in tipping the balance between granulocytic and monocytic development, respectively. 36 Our results support a role of Mef2c as a secondary determinant in determining monocytic fate by simultaneously supporting the monocytic differentiation program and inhibiting granulopoiesis.…”

Section: Discussionmentioning

confidence: 99%

The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate

Schüler

Schwieger

Engelmann

et al. 2008

Blood

View full text Add to dashboard Cite

Mef2c is a MADS (MCM1-agamous IntroductionHematopoiesis is a tightly regulated system in which mature blood cells are constantly replenished from hematopoietic stem cells in the bone marrow, and which responds quickly to foreign invasion or environmental stress. The molecular pathways controlling normal and stress-related hematopoiesis are often targets of oncogenic lesions, the accumulation of which leads to leukemia. In particular, transcriptions factors that play pivotal roles in regulating the differentiation of myeloid cells into active mediators of the innate immune system-granulocytes, macrophages (developing through monocytes), and dendritic cells-are frequently deregulated in acute myeloid leukemia (AML). 1,2 These include the Ets-family member PU.1, the Runt transcription factor RUNX1, the interferon-regulatory factor-8 (IRF-8), and the basic leucine zipper protein (bZIP) factors C/EBP␣, c-JUN, and JUNB. Extensive cross-talk exists between these transcription factors-most likely enabling a quick and expedient response to stress signals, but also ensuring the return to homeostasis. Understanding the complex controls of monocytic and granulocytic differentiation not only provides insight into the innate immune response but also into AML.Recent studies have revealed a role of myocyte enhancer factor 2 (MEF2) transcription factors in acute leukemia. The gene encoding Mef2d has been identified at the breakpoint of a variant t(1;19) in acute lymphoblastic leukemia (ALL), [3][4][5] and the gene encoding Mef2c has recently been shown to be up-regulated in leukemic stem cells of MLL-associated leukemia (Krivtsov et al 6 and M.S., A.S., M. Forster, A.E., M.A., R. Delwel, J. Löhler, R. Slany, E.N.O., and C.S., manuscript submitted), which is associated with myelomonocytic or monocytic phenotypes. 7 Interestingly, both genes have been found as targets of retroviral integration sites in leukemia induced by murine leukemia virus. 8 The Mef2 proteins belong to a distinct class of the MADS (MCM1-agamous-deficient serum response factor) family of transcription factors, and were originally identified as important regulators of myogenic differentiation. 9 There are 4 vertebrate MEF2 genes, which are expressed in distinct but overlapping patterns during embryogenesis. Similar to other MADS domain proteins, MEF2 proteins associate with a variety of transcription cofactors to control specific sets of downstream target genes-and their activity is profoundly influenced by developmental cues and signals from the extracellular environment through several transcriptional and posttranslational controls. 10 The importance of Mef2c in the development of skeletal, cardiac, and smooth muscle is well documented, 9 and more recently, its role in craniofacial and bone development has been revealed. 11,12 Accumulating evidence also supports the importance of MEF2 transcription factors in neuronal differentiation and survival 13,14 and in mediating T-cell receptor-mediated apoptosis and cytokine expression 15,16 ; however, their role in n...

show abstract

“…Use of a regulated C/EBPa transgene and lineage depletion only after transduction in this protocol minimizes biases due to lineage-specific cell cycle inhibition. Consistent with the conclusion that C/EBPa can direct monopoiesis as well as granulopoiesis, transduction of B-or T-cell progenitors with C/EBPa induces macrophage but not neutrophil development (Heavey et al, 2003;Xie and Graf, 2004;Laiosa et al, 2006); transplantation of mice with marrow transduced with C/EBPa increases the proportion of monocytes from 13 to 88%, while inhibiting erythropoiesis (Suh et al, 2006); and CLP or MEP isolated from mice expressing a C/EBPa-ER(T) transgene from the H2K promoter develop into macrophages upon exposure to 4-hydroxytamoxifen (Fukuchi et al, 2006). In contrast, C/EBPa-ER converts CD71…”

Section: Ccaat/enhancer-binding Protein a B And Ementioning

confidence: 99%