C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence

Ye, Min; Zhang, Hong; Amabile, Giovanni; Yang, Henry; Staber, Philipp B.; Zhang, Pu; Levantini, Elena; Alberich-Jordà, Meritxell; Zhang, Junyan; Kawasaki, Akira; Tenen, Daniel G.

doi:10.1038/ncb2698

Cited by 133 publications

(121 citation statements)

References 41 publications

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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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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 also controls fetal liver HSC self-renewal as C/EBPα -/-HSCs show increased competitive repopulation activity in transplanted mice (Zhang et al, 2004). Very recently, using a conditional knockout mouse, it has been shown that C/EBPα is essential for the formation and maintenance of adult HSCs (Ye et al, 2013).…”

Section: Ccaat/enhancer-binding Protein Alphamentioning

confidence: 99%

C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells

Stefano

Sardina

Oevelen

et al. 2013

Nature

190

210

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“…TLR4 activation and ligands are elevated in patients with diabetic (48,49). TLR4 activation in myeloid cells results in suppression of CEBPA and its target genes (50), while in HSPCs, low-dose LPS, absence of CEBPA, and streptozotocininduced diabetes are associated with an expanded longterm hematopoietic stem cell population (51)(52)(53). Together, these data suggest that examining the connection between chronic TLR4 activation in diabetes and its consequences for Cebpa expression and myeloid maturation may be important.…”

Section: Discussionmentioning

confidence: 93%

Diabetes Inhibits Gr-1+ Myeloid Cell Maturation viaCebpaDeregulation

et al. 2015

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Recruitment of innate immune cells from the bone marrow (BM) to an injury site is required for effective repair. In diabetes, this process is altered, leading to excessive recruitment and retention of dysfunctional myeloid cells that fail to promote angiogenesis, prolong inflammation, and block healing. The aberrant myeloid phenotype is partially mediated by stable intrinsic changes to developing cells in the BM that are induced by the diabetic (db) environment, but the exact mechanisms remain largely unknown. Here, we show that the db-derived Gr-1+CD11b+ immature myeloid population has widespread misexpression of chromatin-remodeling enzymes and myeloid differentiation factors. Crucially, diabetes represses transcription of the key myeloid transcription factor CEBPA via diminished H3 Lys 27 promoter acetylation, leading to a failure in monocyte and granulocyte maturation. Restoring Cebpa expression by granulocyte colony-stimulating factor reverses the db phenotype and rescues myeloid maturation. Importantly, our data demonstrate a possible link between myeloid cell maturation and chronic inflammation.

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C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence

Cited by 133 publications

References 41 publications

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

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

C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells

Diabetes Inhibits Gr-1+ Myeloid Cell Maturation viaCebpaDeregulation

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