Enhancement of Hematopoietic Stem Cell Repopulating Capacity and Self-Renewal in the Absence of the Transcription Factor C/EBPα

Zhang, Pu; Iwasaki-Arai, Junko; Iwasaki, Hiromi; Fenyus, Maris; Dayaram, Tajhal; Owens, Bronwyn M.; Shigematsu, Hirokazu; Levantini, Elena; Huettner, Claudia S.; Lekstrom-Himes, Julie; Akashi, Koichi; Tenen, Daniel G.

doi:10.1016/j.immuni.2004.11.006

Cited by 456 publications

(529 citation statements)

References 41 publications

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“…This committed myeloid progenitor is crucial for leukemia initiation as Cebpa knockout mice, lacking myeloid differentiation downstream of the common myeloid progenitor, do not develop AML. 8 The findings in our murine AML model are very much in accordance with observations recently made by investigating the subpopulations with leukemia-initiating potential in human AML samples. This study showed that GMPs and lymphoid-primed MPPs both had leukemia-initiating potential and that these populations are organized in a hierarchical order.…”

Section: Discussionsupporting

confidence: 91%

“…7 Deletion of the Cebpa gene in murine HSCs was found to increase their ability to compete against wild-type HSCs. 8 However, null mutations are virtually never found in CEBPA mutant AML. Affirmatively, in the absence of C/EBPa, no AML was observed in a transgenic mouse model, probably because of the requirement of C/EBPa for myeloid lineage commitment in the pathogenesis of AML.…”

Section: Introductionmentioning

confidence: 99%

“…Affirmatively, in the absence of C/EBPa, no AML was observed in a transgenic mouse model, probably because of the requirement of C/EBPa for myeloid lineage commitment in the pathogenesis of AML. 8,9 The molecular mechanisms behind CEBPA mutations in AML development are not entirely clear. The spectrum of CEBPA mutations observed in AML includes N-terminal mutations blocking the translation of the 42 kDa isoform (p42) while allowing the 30 kDa isoform (p30) to be expressed, and C-terminal mutations generating in-frame insertions/deletions within the basic region leucine zipper DNA binding domain disrupting dimerization and DNA binding of both isoforms.…”

Section: Introductionmentioning

confidence: 99%

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Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPa) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPa mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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“…At the HSC stage, C/EBPα acts to prime HSCs for differentiation along the myeloid lineage via DNA binding to regulatory regions of genes induced during differentiation (16). Although conditional Cebpa knockout mice do not develop disease, the loss of Cebpa in adult HSCs leads to an increased number of functional and proliferative HSCs (15,17) and loss of HSC pool maintenance in serial transplantations (16). Cebpa expression is required for AML disease initiation by the oncogene MLL-ENL but not for disease maintenance (18).…”

Section: Introductionmentioning

confidence: 99%

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

et al. 2016

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C/EBPα (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBPα p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive.Using mouse genetics our data reveal that in the complete absence of C/EBPα TRIB2 was unable to induce AML. Only in the presence of C/EBPα p42 and p30 were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate the molecular mechanism involved in degradation of C/EBPα p42 requires site-specific direct interaction between TRIB2 and C/EBPα p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBPα p42. This interaction and ubiquitination is dependent on a critical C-terminal lysine residue on C/EBPα. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2 positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML and the direct interaction and degradation of C/EBPα p42 is required for TRIB2-mediated AML.

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“…C/EBPa exemplifies a transcription factor with distinct roles in normal and leukemic cells because it regulates the balance between differentiation and proliferation in the early stages of normal myelopoiesis 5,7 but is functionally or genetically inactivated in many types of myeloid leukemia in which the homeostatic coordination between proliferation and differentiation is lost. 8,9 Moreover, when ectopically expressed it induces differentiation and inhibits proliferation of myeloid leukemia lines and primary cells from patients with chronic myelogenous leukemia (CML)-blast crisis.…”

Section: Introductionmentioning

confidence: 99%

Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1

et al. 2012

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Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein.STAT 5B and Mcl-1, two genes important for the proliferation and survival of hematopoietic stem cells, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34 þ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34 þ CML cells.

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Enhancement of Hematopoietic Stem Cell Repopulating Capacity and Self-Renewal in the Absence of the Transcription Factor C/EBPα

Cited by 456 publications

References 41 publications

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1

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