Antagonistic effect of CCAAT enhancer-binding protein-α and Pax5 in myeloid or lymphoid lineage choice in common lymphoid progenitors

Hsu, Chia Lin; Fleischman, Angela G.; Lai, Anne Y.; Matsumoto, Yukie; Weissman, Irving L.; Kondo, Motonari

doi:10.1073/pnas.0510304103

Cited by 60 publications

(52 citation statements)

References 36 publications

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“…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: 62%

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

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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 ...

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Section: Discussionmentioning

confidence: 62%

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

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“…6). In contrast, the generation of B cells in OP9-DL lo cocultures can be explained by the high levels of Pax5 expression, acting to repress Notch1 expression (48) and inhibit C/EBPa function (49). However, the increased generation of myeloid cells in OP9-DL med suggests that sufficient Notch signaling activation results in Pax5 repression, which together with the available, albeit lower, levels of Cebpa provides a permissive transcriptional program to allow for myelopoiesis.…”

Section: Dll4 Is More Efficient Than Dll1 In T Lymphopoiesis Inductionmentioning

confidence: 97%

Direct Comparison of Dll1- and Dll4-Mediated Notch Activation Levels Shows Differential Lymphomyeloid Lineage Commitment Outcomes

Mohtashami

Shah

Nakase

et al. 2010

The Journal of Immunology

145

148

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In the thymus, Notch signaling is essential for T lymphopoiesis, with Delta-like (Dll)4 uniquely involved in this process. However, using cocultures, either Dll4 or Dll1 were shown to support T lymphopoiesis. To address which Dll is more effective at inducing hematopoietic progenitor cells to give rise to T lineage cells in vitro, we generated OP9 cells expressing a series of incrementally discrete and equivalent levels of Dll1 or Dll4. In keeping with previous findings, OP9 cells expressing high levels of either Dll1 or Dll4 gave rise to T lineage cells with similar efficacy, and prevented the differentiation of B and myeloid-lineage cells. However, at limiting levels, Dll4 maintained its ability to inhibit B lineage choice and induce T lineage commitment and differentiation at lower levels than Dll1. This manifest property of Dll4 is evident despite lower levels of steady-state surface expression than Dll1 on OP9 cells. The heightened effectiveness of Dll4 over Dll1 also corresponded to the induction of Notch target genes, and inhibition of B and myeloid-specific transcription factors. Furthermore, we show that OP9 cells expressing levels of Dll4 equivalent to those present in thymic epithelial cells, as expected, gave rise to T lineage cells, but were also permissive for the differentiation of myeloid cells; whereas, still inhibiting B lymphopoiesis. Our findings show that Dll4 expressed at physiological levels on OP9 cells is functionally distinct from similarly expressed levels of Dll1, illustrating the unique properties of Dll4 in supporting the combined T lineage and specific myeloid-lineage outcomes that underpin its function within the thymus.

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“…C/EBPa also binds and activates its own promoter, perhaps reflecting a feedforward mechanism to fix commitment decisions (Christy et al, 1991). As a further means of stabilizing commitment decisions, cross-inhibition of C/EBPa and Pax5 expression may stabilize transition of LMP to either the CLP or GMP stages, although the extent of such competition and the mechanisms involved require further investigation (Heavey et al, 2003;Xie and Graf, 2004;Hsu et al, 2006;Anderson et al, 2007). Pax5 also represses the MCSFR promoter through direct interaction (Tagoh et al, 2006).…”

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

confidence: 99%

Transcriptional control of granulocyte and monocyte development

2007

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Antagonistic effect of CCAAT enhancer-binding protein-α and Pax5 in myeloid or lymphoid lineage choice in common lymphoid progenitors

Cited by 60 publications

References 36 publications

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

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

Direct Comparison of Dll1- and Dll4-Mediated Notch Activation Levels Shows Differential Lymphomyeloid Lineage Commitment Outcomes

Transcriptional control of granulocyte and monocyte development

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